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Product Name
:
ALSAVAL
Chemical Name
:
Diazepam
Therapeutic Category
:
Central nervous system drugs
Pharmacologic Category
:
Benzodiazepine
Pharmaceutical Form
:
Vial
Composition
:
Diazepam 10mg/2ml
Dosing
 
Dosing: Adult

Anxiety (symptoms/disorders): Oral, I.M, I.V.: 2-10 mg 2-4 times/day if needed

Muscle spasm: I.V., I.M.: Initial: 5-10 mg; then 5-10 mg in 3-4 hours, if necessary. Larger doses may be required if associated with tetanus.

Sedation in the ICU patient: I.V.: 0.03-0.1 mg/kg every 30 minutes to 6 hours (Jacobi, 2002)

Status epilepticus:

I.V.: 5-10 mg every 5-10 minutes given over ≤5 mg/minute (maximum dose: 30 mg)

 
Dosing: Pediatric
Conscious sedation for procedures:

I.V.: Adolescents: 5 mg; may repeat with 2.5 mg if needed

Muscle spasm associated with tetanus: I.V., I.M.:

Infants >30 days and Children <5 years: 1-2 mg/dose every 3-4 hours as needed

Children ≥5 years: 5-10 mg/dose every 3-4 hours as needed
Sedation or muscle relaxation or anxiety:

I.M., I.V.: Children: 0.04-0.3 mg/kg/dose every 2-4 hours to a maximum of 0.6 mg/kg within an 8-hour period if needed

Status epilepticus:

I.V.: Infants >30 days and Children: 0.1-0.3 mg/kg (maximum dose: 10 mg) given over ≤5 mg/minute; may repeat dose after 5-10 minutes (Hegenbarth, 2008)

Manufacturer's recommendations:

Infants >30 days and Children <5 years: 0.2-0.5 mg given slowly every 2-5 minutes (maximum total dose: 5 mg); repeat in 2-4 hours if needed

Children ≥5 years: 1 mg given slowly every 2-5 minutes (maximum total dose: 10 mg); repeat in 2-4 hours if needed

Dosing: Geriatric
Oral absorption is more reliable than I.M.
Dosing: Renal Impairment

No dose adjustment recommended; decrease dose if administered for prolonged periods.

I.V.: Risk of propylene glycol toxicity; monitor closely if using for prolonged periods or at high doses.

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

Dosing: Hepatic Impairment

Decrease maintenance dose by 50%; half-life significantly prolonged.

Use
 

Management of anxiety disorders, ethanol withdrawal symptoms; skeletal muscle relaxant; treatment of convulsive disorders; preoperative or preprocedural sedation and amnesia

Use - Unlabeled/Investigational

Panic disorders; short-term treatment of spasticity in children with cerebral palsy; sedation for mechanically-ventilated patients in the intensive care unit

Adverse Reactions
 

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

Cardiovascular: Hypotension, vasodilatation

Central nervous system: Amnesia, ataxia, confusion, depression, drowsiness, fatigue, headache, slurred speech, paradoxical reactions (eg, aggressiveness, agitation, anxiety, delusions, hallucinations, inappropriate behavior, increased muscle spasms, insomnia, irritability, psychoses, rage, restlessness, sleep disturbances, stimulation), vertigo

Dermatologic: Rash
Endocrine & metabolic: Libido changes

Gastrointestinal: Constipation, diarrhea, nausea, salivation changes (dry mouth or hypersalivation)

Genitourinary: Incontinence, urinary retention
Hepatic: Jaundice
Local: Phlebitis, pain with injection
Neuromuscular & skeletal: Dysarthria, tremor, weakness
Ocular: Blurred vision, diplopia
Respiratory: Apnea, asthma, respiratory rate decreased
Contraindications
 
Hypersensitivity to diazepam or any component of the formulation (cross-sensitivity with other benzodiazepines may exist); myasthenia gravis; severe respiratory insufficiency; severe hepatic insufficiency; sleep apnea syndrome; acute narrow-angle glaucoma; not for use in children <6 months of age (oral)
Warnings / Precautions Drug
 
Concerns related to adverse effects:

• Anterograde amnesia: Benzodiazepines have been associated with anterograde amnesia.

• CNS depression: May cause CNS depression, which may impair physical or mental abilities; patients must be cautioned about performing tasks which require mental alertness (eg, operating machinery or driving).

• Psychiatric and paradoxical reactions: Reactions, including hyperactive or aggressive behavior, hallucinations, and psychoses, have been reported with benzodiazepines, particularly in adolescent/pediatric or elderly patients. Diazepam should be discontinued if reactions occur.

Disease-related concerns:

• Convulsive disorders: When used as an adjunct in treating convulsive disorders, an increase in frequency/severity of grand mal seizures may occur and require dose adjustment of anticonvulsant. Abrupt withdrawal may result in a temporary increase of seizures.

• Depression: Use caution in patients with depression or anxiety associated with depression, particularly if suicidal risk may be present.

• Drug abuse: Use with caution in patients with a history of drug abuse or acute alcoholism; potential for drug dependency exists. Tolerance, psychological and physical dependence may occur with prolonged use (generally >10 days).

• Hepatic impairment: Use with caution in patients with hepatic impairment.

• Impaired gag reflex: Use with caution in patients with an impaired gag reflex.

• Renal impairment: Use with caution in patients with renal impairment.

• Respiratory disease: Use with caution in patients with respiratory disease; a lower dose is recommended for chronic respiratory insufficiency.

Concurrent drug therapy issues:

• CNS depressants/psychoactive medications: Use with caution in patients receiving other CNS depressants or psychoactive medication; effects with other sedative drugs or ethanol may be potentiated.

• High potential for interactions: Use with caution in patients taking strong CYP3A4 inhibitors, moderate or strong CYP3A4 and CYP2C19 inducers and major CYP3A4 substrates (see Drug Interactions); consider alternative agents that avoid or lessen the potential for CYP-mediated interactions.

• Narcotics: The dosage of narcotics should be reduced by approximately one-third when diazepam is added.

Special populations:

• Debilitated/elderly patients: Use with caution; active metabolites with extended half-lives may lead to delayed accumulation and adverse effects; limit dose to smallest effective amount (2-2.5 mg once or twice daily initially, to be increased gradually and as tolerated) to avoid adverse reactions.

• Elderly: Benzodiazepines with long half-lives may produce prolonged sedation and increase the risk of falls and fracture. Short- or intermediate-acting benzodiazepines are preferred in elderly patients (Beers Criteria).

• Fall risk: Use with extreme caution in patients who are at risk of falls; benzodiazepines have been associated with falls and traumatic injury.

• Neonates: Safety and efficacy of the injection have not been established in children <1 month of age. Solution for injection may contain sodium benzoate, benzyl alcohol, or benzoic acid. Large amounts have been associated with “gasping syndrome” in neonates.

• Obese patients: Use with caution in obese patients; may have prolonged action when discontinued.

• Psychotic patients: Use of diazepam is not recommended in place of appropriate therapy.

Dosage form specific issues:

• Parenteral: Acute hypotension, muscle weakness, apnea, and cardiac arrest have occurred with parenteral administration. Acute effects may be more prevalent in patients receiving concurrent barbiturates, narcotics, or ethanol. Appropriate resuscitative equipment and qualified personnel should be available during administration and monitoring. Avoid use of the injection in patients with shock, coma, or acute ethanol intoxication. Intra-arterial injection or extravasation of the parenteral formulation should be avoided. Parenteral formulation contains propylene glycol, which has been associated with toxicity when administered in high dosages.

• Propylene glycol: Parenteral formulation contains propylene glycol. May be associated with toxicity in high-dose and/or longer-term therapy.

• Rectal gel: Administration of rectal gel should only be performed by individuals trained to recognize characteristic seizure activity for which the product is indicated, and capable of monitoring response to determine need for additional medical intervention.

Other warnings/precautions:

• Appropriate use: Does not have analgesic, antidepressant, or antipsychotic properties.

• Withdrawal: Rebound or withdrawal symptoms may occur following abrupt discontinuation or large decreases in dose. Use caution when reducing dose or withdrawing therapy; decrease slowly and monitor for withdrawal symptoms. Flumazenil may cause withdrawal in patients receiving long-term benzodiazepine therapy.

Interactions
 

Alcohol (Ethyl): CNS Depressants may enhance the CNS depressant effect of Alcohol (Ethyl). Risk C: Monitor therapy

Antifungal Agents (Azole Derivatives, Systemic): May decrease the metabolism of Benzodiazepines (metabolized by oxidation). Management: The following combinations are specifically contraindicated: itraconazole with alprazolam, estazolam, oral midazolam, or triazolam; ketoconazole with alprazolam, estazolam, or triazolam. Consider initial dose reductions of other benzodiazepines. Risk D: Consider therapy modification

Aprepitant: May increase the serum concentration of Benzodiazepines (metabolized by oxidation). Risk C: Monitor therapy

Calcium Channel Blockers (Nondihydropyridine): May decrease the metabolism of Benzodiazepines (metabolized by oxidation). Exceptions: Bepridil [Off Market]. Risk D: Consider therapy modification

CarBAMazepine: May increase the metabolism of Benzodiazepines (metabolized by oxidation). Risk C: Monitor therapy

Cimetidine: May decrease the metabolism of Benzodiazepines (metabolized by oxidation). Risk C: Monitor therapy

CloZAPine: Benzodiazepines may enhance the adverse/toxic effect of CloZAPine. Management: Consider decreasing the dose of (or possibly discontinuing) benzodiazepines prior to initiating clozapine. Risk D: Consider therapy modification

CNS Depressants: May enhance the adverse/toxic effect of other CNS Depressants. Exceptions: Levocabastine (Nasal). Risk C: Monitor therapy

Conivaptan: May increase the serum concentration of CYP3A4 Substrates. Risk X: Avoid combination

Contraceptives (Estrogens): May decrease the metabolism of Benzodiazepines (metabolized by oxidation). Risk C: Monitor therapy

Contraceptives (Progestins): May increase the serum concentration of Benzodiazepines (metabolized by oxidation). Risk C: Monitor therapy

CYP2C19 Inducers (Strong): May increase the metabolism of CYP2C19 Substrates. Risk C: Monitor therapy

CYP2C19 Inhibitors (Moderate): May decrease the metabolism of CYP2C19 Substrates. Risk C: Monitor therapy

CYP2C19 Inhibitors (Strong): May decrease the metabolism of CYP2C19 Substrates. Risk D: Consider therapy modification

CYP3A4 Inducers (Strong): May increase the metabolism of CYP3A4 Substrates. Risk C: Monitor therapy

CYP3A4 Inhibitors (Moderate): May decrease the metabolism of CYP3A4 Substrates. Risk C: Monitor therapy

CYP3A4 Inhibitors (Strong): May decrease the metabolism of CYP3A4 Substrates. Risk D: Consider therapy modification

Cyproterone: May decrease the serum concentration of CYP1A2 Substrates. Risk C: Monitor therapy

Dasatinib: May increase the serum concentration of CYP3A4 Substrates. Risk C: Monitor therapy

Deferasirox: May decrease the serum concentration of CYP3A4 Substrates. Risk C: Monitor therapy

Disulfiram: May increase the serum concentration of Diazepam. Risk C: Monitor therapy

Droperidol: May enhance the CNS depressant effect of CNS Depressants. Management: Consider dose reductions of droperidol or of other CNS agents (e.g., opioids, barbiturates) with concomitant use. Risk D: Consider therapy modification

Fluconazole: May decrease the metabolism of Benzodiazepines (metabolized by oxidation). Risk D: Consider therapy modification

Fosamprenavir: May increase the serum concentration of Diazepam. Risk C: Monitor therapy

Fosaprepitant: May increase the serum concentration of Benzodiazepines (metabolized by oxidation). Specifically, the active metabolite aprepitant is likely responsible for this effect. Risk C: Monitor therapy

Fosphenytoin: Benzodiazepines may increase the serum concentration of Fosphenytoin. Short-term exposure to benzodiazepines may not present as much risk as chronic therapy. Risk C: Monitor therapy

Grapefruit Juice: May decrease the metabolism of Benzodiazepines (metabolized by oxidation). Risk D: Consider therapy modification

HydrOXYzine: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Isoniazid: May decrease the metabolism of Benzodiazepines (metabolized by oxidation). Risk C: Monitor therapy

Macrolide Antibiotics: May decrease the metabolism of Benzodiazepines (metabolized by oxidation). Exceptions: Azithromycin; Azithromycin (Systemic); Fidaxomicin (Systemic); Spiramycin. Risk D: Consider therapy modification

Methotrimeprazine: CNS Depressants may enhance the CNS depressant effect of Methotrimeprazine. Methotrimeprazine may enhance the CNS depressant effect of CNS Depressants. Management: Reduce adult dose of CNS depressant agents by 50% with initiation of concomitant methotrimeprazine therapy. Further CNS depressant dosage adjustments should be initiated only after clinically effective methotrimeprazine dose is established. Risk D: Consider therapy modification

Nefazodone: May decrease the metabolism of Benzodiazepines (metabolized by oxidation). Risk D: Consider therapy modification

OLANZapine: May enhance the adverse/toxic effect of Benzodiazepines. Management: Avoid concomitant use of parenteral benzodiazepines and IM olanzapine due to risks of additive adverse events (e.g., cardiorespiratory depression). Olanzapine prescribing information provides no specific recommendations regarding oral administration. Risk X: Avoid combination

Phenytoin: Benzodiazepines may increase the serum concentration of Phenytoin. Short-term exposure to benzodiazepines may not present as much risk as chronic therapy. Risk C: Monitor therapy

Proton Pump Inhibitors: May increase the serum concentration of Benzodiazepines (metabolized by oxidation). Exceptions: Lansoprazole; Pantoprazole; RABEprazole. Risk C: Monitor therapy

Rifamycin Derivatives: May increase the metabolism of Benzodiazepines (metabolized by oxidation). Risk D: Consider therapy modification

Ritonavir: May increase the serum concentration of Diazepam. Risk C: Monitor therapy

Saquinavir: May increase the serum concentration of Diazepam. Risk C: Monitor therapy

Selective Serotonin Reuptake Inhibitors: May decrease the metabolism of Benzodiazepines (metabolized by oxidation). Exceptions: Citalopram; Escitalopram; PARoxetine; Sertraline. Risk C: Monitor therapy

Selective Serotonin Reuptake Inhibitors: CNS Depressants may enhance the adverse/toxic effect of Selective Serotonin Reuptake Inhibitors. Specifically, the risk of psychomotor impairment may be enhanced. Risk C: Monitor therapy

St Johns Wort: May increase the metabolism of Benzodiazepines (metabolized by oxidation). Risk C: Monitor therapy

Theophylline Derivatives: May diminish the therapeutic effect of Benzodiazepines. Risk D: Consider therapy modification

Tocilizumab: May decrease the serum concentration of CYP3A4 Substrates. Risk C: Monitor therapy

Yohimbine: May diminish the therapeutic effect of Antianxiety Agents. Risk C: Monitor therapy

Pregnancy
 
D
Pregnancy Implications

Teratogenic effects have been reported in animal studies. In humans, diazepam and its metabolites (N-desmethyldiazepam, temazepam, and oxazepam) cross the placenta. Teratogenic effects have been observed with diazepam; however, additional studies are needed. The incidence of premature birth and low birth weights may be increased following maternal use of benzodiazepines; hypoglycemia and respiratory problems in the neonate may occur following exposure late in pregnancy. Neonatal withdrawal symptoms may occur within days to weeks after birth and “floppy infant syndrome” (which also includes withdrawal symptoms) has been reported with some benzodiazepines (including diazepam).

Lactation
 

Enters breast milk/not recommended (AAP rates “of concern”; AAP 2001 update pending)

Breast-Feeding Considerations
Diazepam and N-desmethyldiazepam can be found in breast milk; the oxazepam metabolite has also been detected in the urine of a nursing infant. Drowsiness, lethargy, or weight loss in nursing infants have been observed in case reports following maternal use of some benzodiazepines, including diazepam.
Monitoring Parameters
 

Respiratory, cardiovascular, and mental status; check for orthostasis

Reference Range
Therapeutic: Diazepam: 0.2-1.5 mcg/mL (SI: 0.7-5.3 micromole/L); N-desmethyldiazepam (nordiazepam): 0.1-0.5 mcg/mL (SI: 0.35-1.8 micromole/L)
Mechanism of Action
 
Binds to stereospecific benzodiazepine receptors on the postsynaptic GABA neuron at several sites within the central nervous system, including the limbic system, reticular formation. Enhancement of the inhibitory effect of GABA on neuronal excitability results by increased neuronal membrane permeability to chloride ions. This shift in chloride ions results in hyperpolarization (a less excitable state) and stabilization.
Pharmacodynamics / Kinetics
 
I.V.: Status epilepticus:
Onset of action: Almost immediate
Duration: 20-30 minutes
Absorption: Oral: 85% to 100%, more reliable than I.M.
Protein binding: 98%
Metabolism: Hepatic
Half-life elimination: Parent drug: Adults: 20-50 hours; increased half-life in neonates, elderly, and those with severe hepatic disorders; Active major metabolite (desmethyldiazepam): 50-100 hours; may be prolonged in neonates
 
   
 
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