VALOXIUM

A benzodiazepine with anticonvulsant, anxiolytic, sedative, muscle relaxant, and amnesic properties and a long duration of action.

Its actions are mediated by enhancement of gamma-aminobutyric acid activity.

It is used in the treatment of severe anxiety disorders, as a hypnotic in the short-term management of insomnia, as a sedative and premedicant, as an anticonvulsant, and in the management of alcohol withdrawal syndrome. (From Martindale, The Extra Pharmacopoeia, 30th ed, p589) Given diazepam's storied history as a commonly used and effective medication for a variety of indications, contemporary advancements in the formulation and administration of the agent include the development and US FDA approval of an auto-injectable formulation for the rapid treatment of uncontrolled seizures in 2015-2016 7.

Combining diazepam, a proven effective therapy for acute repetitive seizures, with an auto-injector designed for subcutaneous administration that is quickly and easily administered offers the potential for complete, consistent drug absorption and rapid onset of effect 7.

This current development is subsequently an important addition to the rescue therapy tool chest for patients with epilepsy 7.

In general, diazepam is useful in the symptomatic management of mild to moderate degrees of anxiety in conditions dominated by tension, excitation, agitation, fear, or aggressiveness such as may occur in psychoneurosis, anxiety reactions due to stress conditions, and anxiety states with somatic expression.

Moreover, in acute alcoholic withdrawal, diazepam may be useful in the symptomatic relief of acute agitation, tremor, and impending acute delirium tremens.

Furthermore, diazepam is a useful adjunct for the relief of skeletal muscle spasm due to reflex spasm to local pathologies, such as inflammation of the muscle and joints or secondary to trauma; spasticity caused by upper motor neuron disorders, such as cerebral palsy and paraplegia; athetosis and the rare "stiff man syndrome".

Particular label information from the United

Kingdom also lists particular age-specific indications, including for adults: The short-term relief (2-4 weeks) only, of anxiety which is severe, disabling, or subjecting the individual to unacceptable distress, occurring alone or in association with insomnia or short-term psychosomatic, organic or psychotic illness, cerebral palsy, muscle spasm, as an adjunct to certain types of epilepsy (eg. myoclonus), symptomatic treatment of acute alcohol withdrawal, as oral premedication for the nervous dental patient, and for premedication before surgery.

In the same

UK label information, diazepam is indicated in children for: control of tension and irritability in cerebral spasticity in selected cases, as an adjunct to the control of muscle spasm in tetanus, and for oral premedication.

A diazepam nasal spray is indicated in patients 6 years and older to treat intermittent, stereotypic episodes of frequent seizure activity that are different than the patient's usual seizure pattern.

Diazepam is a benzodiazepine that exerts anxiolytic, sedative, muscle.

• relaxant, anticonvulsant and amnestic effects 15, 16, 6.

Most of these effects are thought to result from facilitation of the action of gamma aminobutyric acid (GABA), an inhibitory neurotransmitter in the central nervous system 15, 16, 6.

Receptor Positive allosteric modulator

GABA(A) Receptor Benzodiazepine Binding Site Ligand.

After oral administration, it is considered that diazepam is rapidly and completely absorbed from the gastrointestinal tract as >90% of diazepam is absorbed and the average time to achieve peak plasma concentrations is 1 – 1.5 hours with a range of 0.25-2.5 hours 15, 16, 6.

Absorption is delayed and decreased when administered with a moderate fat meal 15.

In the presence of food mean lag times are approximately 45 minutes as compared with 15 minutes when fasting 15.

There is also an increase in the average time to achieve peak concentrations to about 2.5 hours in the presence of food as compared with 1.25 hours when fasting 15.

This results in an average decrease in Cmax of 20% in addition to a 27% decrease in AUC (range 15% to 50%) when administered with food 15.

In young healthy males, the volume of distribution at steady-state is 0.8-1.0 L/kg 15.

Diazepam is N-demethylated by

CYP3A4 and 2C19 to the active metabolite N-desmethyldiazepam, and is hydroxylated by CYP3A4 to the active metabolite temazepam 15, 16.

N-desmethyldiazepam and temazepam are both further metabolized to oxazepam 15, 16.

Temazepam and oxazepam are further largely eliminated by way of conjugation to glucuronic acid via glucuronidation 15, 16.

Furthermore, oxidation of diazepam is mediated by cytochrome P450 isozymes; formation of desmethyl-diazepam mainly by CYP2C19 and CYP3A and 3-hydroxy-diazepam (temazepam) and oxazepam by CYP3A.

CYP2C19 is polymorphic, extensive metabolizers (EMs), and poor metabolizers (PMs) of diazepam can be distinguished 15, 16.

PMs of diazepam showed significantly lower clearance (12 vs 26 mL/min) and longer elimination half-life (88 vs 41 h) of diazepam than EMs after a single oral dose 15, 16.

Also, PMs had lower clearance, higher AUC and longer elimination half-life of desmethyl-diazepam 15, 16.

Hover over products below to view reaction partners Diazepam Nordazepam Nordiazepam O-glucuronide Oxazepam Temazepam Oxazepam Oxazepam desmethyldiazepam.

Diazepam and its metabolites are excreted mainly in the urine, predominantly as their glucuronide conjugates 15, 16, 6.

Diazepam has a biphasic half-life with an initial rapid distribution phase followed by a prolonged terminal elimination phase of 1 or 2 days; its action is further prolonged by the even longer half-life of 2-5 days of its principal active metabolite, desmethyldiazepam (nordiazepam), the relative proportion of which increases in the body on long-term administration 6.

The plasma half-life of diazepam is prolonged in neonates, in the elderly, and in patients with kidney or liver disease 6.

The clearance of diazepam is 20-30 mL/min in young adults 15, 16.

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The symptoms of diazepam overdose are mainly an intensification of the therapeutic effects (ataxia, drowsiness, dysarthria, sedation, muscle weakness, profound sleep, hypotension, bradycardia, nystagmus) or paradoxical excitation 15, 16, 6.

In most cases only observation of vital functions is required 15, 16, 6.

Extreme overdosage may lead to coma, areflexia, cardio-respiratory depression and apnoea, requiring appropriate countermeasures (ventilation, cardiovascular support) 15, 16, 6.

Benzodiazepine respiratory depressant effects are more serious in patients with severe chronic obstructive airways disease 15, 16, 6.

Severe effects in overdose also include rhabdomyolysis and hypothermia 6.

Overdose of benzodiazepines in combination with other CNS depressants (including alcohol) may be fatal and should be closely monitored 15.

In general, the use of diazepam in women of childbearing potential, and more specifically during known pregnancy, should be considered only when the clinical situation warrants the risk to the fetus 15.

The possibility that a woman of childbearing potential may be pregnant at the time of institution of therapy should be considered 15.

If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus 15.

Patients should also be advised that if they become pregnant during therapy or intend to become pregnant they should communicate with their physician about the desirability of discontinuing the drug 15.

Special care must be taken when diazepam is used during labor and delivery, as high single doses may produce irregularities in the fetal heart rate and hypotonia, poor sucking, hypothermia, and moderate respiratory depression in the neonates 15.

With newborn infants it must be remembered that the enzyme system involved in the breakdown of the drug is not yet fully developed (especially in premature infants) 15.

Diazepam passes into breast milk 15.

Breastfeeding is therefore not recommended in patients receiving diazepam 15.

Safety and effectiveness in pediatric patients below the age of 6 months have not been established 15.

In elderly patients, it is recommended that the dosage be limited to the smallest effective amount to preclude the development of ataxia or oversedation (2 mg to 2.5 mg once or twice daily, initially to be increased gradually as needed and tolerated) 15.

Extensive accumulation of diazepam and its major metabolite, desmethyldiazepam, has been noted following chronic administration of diazepam in healthy elderly male subjects.

Metabolites of this drug are known to be substantially excreted by the kidney, and the risk of toxic reactions may be greater in patients with impaired renal function 15.

Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function 15.

Decreases in clearance and protein binding, and increases in volume of distribution and half-life has been reported in patients with cirrhosis 15.

In such patients, a 2.

• to 5.

• fold increase in mean half-life has been reported 15.

Delayed elimination has also been reported for the active metabolite desmethyldiazepam 15.

Benzodiazepines are commonly implicated in hepatic encephalopathy 15.

Increases in half-life have also been reported in hepatic fibrosis and in both acute and chronic hepatitis 15.

Concomitant use of benzodiazepiones, including diazepam tablets, and opioids may result in profound sedation, respiratory depression, coma, and death.

Because of these risks, reserve concomitant prescribing of these drugs in patients for whom alternative treatment options are inadequate.

Observational studies have demonstrated that concomitant use of opioid analgesics and benzodiazepines increases the risk of drug-related mortality compared to use of opioids alone.

If a decision is made to prescribe diazepam tablets concomitantly with opioids, prescribe the lowest effective dosages and minimum durations of concomitant use, and follow patients closely for signs and symptoms of respiratory depression and sedation.

In patients already receiving an opioid analgesic, prescribe a lower initial dose of diazepam tablets than indicated in the absence of an opioid and titrate based on clinical response.

If an opioid is initiated in a patient already taking diazepam tablets, prescribe a lower initial dose of the opioid and titrate based upon clinical response.

Advise both patients and caregivers about the risks of respiratory depression and sedation when diazepam tablets are used with opioids.

Advise patients not to drive or operate heavy machinery until the effects of concomitant use with the opioid have been determined.

Abuse, Misuse, and Addiction The use of benzodiazepines, including diazepam tablets, exposes users to the risks of abuse, misuse, and addiction, which can lead to overdose or death.

Abuse and misuse of benzodiazepines often (but not always) involve the use of doses greater than the maximum recommended dosage and commonly involve concomitant use of other medications, alcohol, and/or illicit substances, which is associated with an increased frequency of serious adverse outcomes, including respiratory depression, overdose, or death.

Before prescribing diazepam tablets and throughout treatment, assess each patient’s risk for abuse, misuse, and addiction (e.g., using a standardized screening tool).

Use of diazepam tablets, particularly in patients at elevated risk, necessitates counseling about the risks and proper use of diazepam tablets along with monitoring for signs and symptoms of abuse, misuse, and addiction.

Prescribe the lowest effective dosage; avoid or minimize concomitant use of CNS depressants and other substances associated with abuse, misuse, and addiction (e.g., opioid analgesics, stimulants); and advise patients on the proper disposal of unused drug.

If a substance use disorder is suspected, evaluate the patient and institute (or refer them for) early treatment, as appropriate.

To reduce the risk of withdrawal reactions, use a gradual taper to discontinue diazepam tablets or reduce the dosage (a patient-specific plan should be used to taper the dose) See DOSAGE AND ADMINISTRATION: Discontinuation or Dosage Reduction of Diazepam Tablets.

Patients at an increased risk of withdrawal adverse reactions after benzodiazepine discontinuation or rapid dosage reduction include those who take higher dosages, and those who have had longer durations of use.

The continued use of benzodiazepines, including diazepam tablets, may lead to clinically significant physical dependence.

Abrupt discontinuation or rapid dosage reduction of diazepam tablets after continued use, or administration of flumazenil (a benzodiazepine antagonist) may precipitate acute withdrawal reactions, which can be life-threatening (e.g., seizures) .

In some cases, benzodiazepine users have developed a protracted withdrawal syndrome with withdrawal symptoms lasting weeks to more than 12 months.

Diazepam tablets are not recommended in the treatment of psychotic patients and should not be employed instead of appropriate treatment.

Since diazepam tablets have a central nervous system depressant effect, patients should be advised against the simultaneous ingestion of alcohol and other CNS-depressant drugs during diazepam tablets therapy.

As with other agents that have anticonvulsant activity, when diazepam tablets are used as an adjunct in treating convulsive disorders, the possibility of an increase in the frequency and/or severity of grand mal seizures may require an increase in the dosage of standard anticonvulsant medication.

Abrupt withdrawal of diazepam tablets in such cases may also be associated with a temporary increase in the frequency and/or severity of seizures.

Use of diazepam tablets late in pregnancy can result in sedation (respiratory depression, lethargy, hypotonia) and/or withdrawal symptoms (hyperreflexia, irritability, restlessness, tremors, inconsolable crying, and feeding difficulties) in the neonate.

Monitor neonates exposed to diazepam during pregnancy or labor for signs of sedation and monitor neonates exposed to diazepam during pregnancy for signs of withdrawal; manage these neonates accordingly.

Diazepam tablets are contraindicated in patients with a known hypersensitivity to diazepam and, because of lack of sufficient clinical experience, in pediatric patients under 6 months of age.

Diazepam tablets are also contraindicated in patients with myasthenia gravis, severe respiratory insufficiency, severe hepatic insufficiency, and sleep apnea syndrome.

They may be used in patients with open-angle glaucoma who are receiving appropriate therapy, but is contraindicated in acute narrow-angle glaucoma.

Dosage should be individualized for maximum beneficial effect.

While the usual daily dosages given below will meet the needs of most patients, there will be some who may require higher doses.

In such cases dosage should be increased cautiously to avoid adverse effects.

Depending upon severity of symptoms—2 mg to 10 mg, 2 to 4 times daily Symptomatic Relief in Acute Alcohol Withdrawal. 10 mg, 3 or 4 times during the first 24 hours, reducing to 5 mg, 3 or 4 times daily as needed.

Spasm. 2 mg to 10 mg, 3 or 4 times daily Adjunctively in Convulsive.

Disorders. 2 mg to 10 mg, 2 to 4 times daily Geriatric Patients, or in the presence of debilitating disease. 2 mg to 2.5 mg, 1 or 2 times daily initially; increase gradually as needed and tolerated.

Because of varied responses to CNS-acting drugs, initiate therapy with lowest dose and increase as required.

Not for use in pediatric patients under 6 months. 1 mg to 2.5 mg, 3 or 4 times daily initially; increase gradually as needed and tolerated.

Discontinuation or Dosage Reduction of Diazepam Tablets To reduce the risk of withdrawal reactions, use a gradual taper to discontinue diazepam tablets or reduce the dosage.

If a patient develops withdrawal reactions, consider pausing the taper or increasing the dosage to the previous tapered dosage level.

Subsequently decrease the dosage more slowly See WARNINGS: Dependence and Withdrawal Reactions and DRUG ABUSE AND DEPENDENCE: Dependence.

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Use of diazepam tablets late in pregnancy can result in sedation (respiratory depression, lethargy, hypotonia) and/or withdrawal symptoms (hyperreflexia, irritability, restlessness, tremors, inconsolable crying, and feeding difficulties) in the neonate.

Monitor neonates exposed to diazepam during pregnancy or labor for signs of sedation and monitor neonates exposed to diazepam during pregnancy for signs of withdrawal; manage these neonates accordingly.

Diazepam is present in breastmilk.

There are reports of sedation, poor feeding, and poor weight gain in infants exposed to benzodiazepines through breast milk.

Because of the potential for serious adverse reaction, including sedation and withdrawal symptoms in breastfed infants, advise patient that breastfeeding is not recommended during treatment with diazepam tablets.

Safety and effectiveness in pediatric patients below the age of 6 months have not been established.

In elderly patients, it is recommended that the dosage be limited to the smallest effective amount to preclude the development of ataxia or oversedation (2 mg to 2.5 mg once or twice daily, initially to be increased gradually as needed and tolerated).

Extensive accumulation of diazepam and its major metabolite, desmethyldiazepam, has been noted following chronic administration of diazepam in healthy elderly male subjects.

Metabolites of this drug are known to be substantially excreted by the kidney, and the risk of toxic reactions may be greater in patients with impaired renal function.

Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.