FDA

• Acute alcohol withdrawal
• Anxiety
• Epilepsy
• Generalized anxiety disorder
• Insomnia
• Muscle spasms
• Panic disorder
• Procedural sedation

NON-FDA APPROVED USES

• Agitation
• Akathisia
• Catatonia
• Dystonia
• Manic episodes

• The dosage of a benzodiazepine will vary depending on the patient, treatment indication, and their history of sedative use.
• Although similar in many ways, the choice of an agent is often based on its pharmacokinetic properties, especially onset of action, half-life, and metabolic pathway.
• Table of Dose Equivalency Estimation (equivalent to 10 mg oral diazepam): consider more conservative dose conversions for high risk patients, e.g. treatment naïve, elderly, impaired hepatic or renal function, concomitant medications, comorbid disease states, etc.

ABSORPTION

• High-fat meals: may delay time to but not extent of absorption of alprazolam
• Moderate-fat meals: may delay and decrease absorption of diazepam
• Grapefruit juice: may increase levels of alprazolam and diazepam

METABOLISM

• Many of the benzodiazepines are metabolized by the P450 system, except Lorazepam, Oxazepam, Temazepam (*memory tip*: the “LOT” benzodiazepines).
• The “LOT” benzodiazepines do not rely on the P450 system for metabolism.
• Undergo glucuronidation to inactive metabolites
• Lack P450 drug interactions
• Lack drug accumulation
• Preferred for patients with significant hepatic impairment
  
  
  Benzodiazepine	Metabolism
  Alprazolam (Xanax)	CYP 3A4
  Chlordiazepoxide (Librium)	Hepatic
  Clonazepam (Klonopin)	CYP 3A4
  Diazepam (Valium)	CYP 3A4, CYP 2C19
  Lorazepam (Ativan)	Hepatic
  Oxazepam (Serax)	Hepatic

HALF-LIFE

• Benzodiazepines differ in their pharmacokinetics, and selection is often determined by the agent’s onset of action and duration of action.
• Half-life may be further prolonged due to hepatic and/or renal impairment and drug interactions, requiring dose adjustments.

DRUG INTERACTIONS

• Cytochrome P450 drug interactions: since most benzodiazepines are metabolized through this system, review risk with specific benzodiazepine agent – they are not listed in the table below
• CNS depressants (e.g. anticonvulsants, barbiturates, benzodiazepines, hypnotics, muscle relaxants, sedative antihistamines, etc.): significant CNS and respiratory depressant effects
• Olanzapine: excessive sedation and cardiorespiratory depression with parenteral benzodiazepines
• Opioids: increased risk of significant respiratory depression, profound sedation, coma and death

Select drug interactions:

COMMON SIDE EFFECTS

• Ataxia
• Dizziness
• Dry mouth
• Dysarthria
• Fatigue
• Hypotension
• Impaired coordination
• Irritability
• Lightheadedness
• Memory impairment
• Sedation

BOXED WARNINGS

• Risk of misuse, abuse, and addiction, which can lead to overdose and death
  • All benzodiazepine agents are Schedule IV controlled substances.
  • Assess patient’s risk before prescribing and reassess risk regularly
  • Abuse and misuse can involve concomitant use of other medications, alcohol and/or illicit substances, which can increase the incidence of serious adverse outcomes.
  • Use cautiously and sparingly in patients with a history of substance use disorder
• Risk of profound sedation, respiratory depression, coma and death from concomitant use with opioids, alcohol, and other CNS depressants (e.g. anticonvulsants, barbiturates, narcotic analgesics, muscle relaxants, sedative antihistamines, etc.):
  • Reserve concomitant use in patients for whom alternative treatment options are inadequate
  • Limit doses and duration of benzodiazepine treatment to the minimum required
  • Monitor patients for signs and symptoms of respiratory depression and sedation
  • Rescue naloxone (i.e. inhalation or injectable) should be offered or provided to minimize risk of overdose
• Abrupt discontinuation or rapid dose reduction after continued use may precipitate acute withdrawal, which can be life threatening: gradually reduce the dose or taper to discontinue.

CONTRAINDICATIONS

PRECAUTIONS

• Dependence and withdrawal reactions:
  • Increased risk with higher doses and longer durations of use, rapid dose reductions, abrupt discontinuation of benzodiazepines, and agents with shorter half-lives
  • May be life threatening, e.g. due to seizures
  • Acute withdrawal reactions may occur with flumazenil (benzodiazepine receptor antagonist).
  • Withdrawal symptoms may occur between doses, e.g. with agents with shorter half-lives such as alprazolam.
  • Protracted withdrawal syndrome can last weeks to months.
• Impairment of ability to drive or operate machinery:
  • Evaluate the mental and physical effects during treatment initiation and dose adjustment before engaging in activities that require alertness and coordination
  • Avoid concomitant use of alcohol and other CNS depressants which can contribute to cognitive impairment
• Impaired respiratory function:
  • Consider lower doses for patients with chronic respiratory insufficiency (e.g. COPD, sleep apnea, etc.) due to risk of respiratory depression
  • Significant respiratory impairment may occur, including rare reports of death, in patients with severe pulmonary disease.
• Persistent or worsening insomnia: may be due to a primary psychiatric and/or medical illness that should be evaluated
• Propylene glycol toxicity: associated with injectables
  • Increased risk with greater than recommended doses and in patients with renal or hepatic dysfunction, impaired alcohol dehydrogenase enzymes, or other comorbidities, including history of alcohol use disorder
  • Associated with anion gap metabolic acidosis, serum hyperosmolality, and increased lactate
  • Can cause acute tubular necrosis, cardiac arrythmias, hypotension, mental status changes, seizures and progression to multiorgan failure
• Tolerance to the therapeutic effects may develop with continued use.

RARE SIDE EFFECTS

• Memory impairment, anterograde amnesia, temporary amnesia: may be dose related and more prevalent with select benzodiazepine agents, e.g. midazolam, triazolam, etc.
• Paradoxical reactions:
  • e.g. aggression, agitation, anxiety, excitation, hallucinations, insomnia, irritability, nightmares, psychosis, etc.
  • Occurs more commonly in children and the elderly
• Porphyria
• Propylene and polyethylene glycol toxicity: risk with lorazepam injectable
  • Increased risk with use of higher than recommended doses and patients with renal impairment
  • Associated with lactic acidosis, hyperosmolality, hypotension, acute tubular necrosis
• Suicidal behavior and ideation:
  • Benzodiazepines do not treat and may worsen depression.
  • Prescribe the least number of tablets needed to avoid intentional overdose

PEDIATRICS

• Not all benzodiazepine agents are FDA approved for use in the pediatric population; however, select agents may be used off label.
• Diazepam: approved for > 6 months of age
• Chlordiazepoxide, oxazepam: approved for > 6 years of age
• Lorazepam:
  • Approved for > 12 years of age
  • However, the safety and efficacy of lorazepam ER (Loreev XR) has not been established
  • Lorazepam injectable is contraindicated in premature infants because it contains benzyl alcohol (risk of hypotension, metabolic acidosis, kernicterus, and, in rare cases, death)
• Start low and titrate slowly; use lowest effective dose for shortest period
• Increased risk of paradoxical reactions

GERIATRICS

• Unless there are compelling reasons for use, avoid or minimize use.
• Start low and titrate slowly; use lowest effective dose for shortest period
• Beers List due to an increased risk of CNS depression, confusion, falls, fractures and risk of side effects and overdose when used with other CNS depressants
• Age-related changes in metabolism and excretion may increase levels and effects.
• Increased risk of paradoxical reactions

PREGNANCY

• Review risk with specific benzodiazepine agent
• Historically, benzodiazepines were assigned Category D; however, more recent evidence shows that teratogenic risk is lower than initially described.
• Weigh the benefit vs. the risk of continued benzodiazepine therapy; if necessary, consider an agent with a short half-life, and use sparingly and intermittently , e.g. reserve for PRN use
• Consider initiating and/or maintaining patients on an antidepressant agent, which are considered safer to use in pregnancy (exception: paroxetine)
• If used through pregnancy and delivery, monitor newborn for neonatal withdrawal syndrome (feeding difficulties, hyperreflexia, inconsolable crying, irritability, restlessness, tremors).

LACTATION

• Review risk with specific benzodiazepine agent
• In general, breastfeeding is not recommended with benzodiazepine treatment due to the risk of sedation and withdrawal symptoms in breastfed infants; however, breastfeeding may mitigate withdrawal symptoms.
• Benzodiazepines are lipophilic and secreted into the breastmilk; if used, select an agent with a shorter half-life.
• Benzodiazepines may have a longer half-life in infants, especially premature newborns who have not developed the mechanisms for metabolism.
• Breastfed infants may experience side effects, including respiratory depression, sedation, lethargy, poor feeding and poor weight gain – monitor accordingly.
• Rare reports of hypotonia - also known as “floppy baby syndrome”