If It Doesn’t Work

• Consider switching to another agent or adding an appropriate augmenting agent

• Consider psychotherapy, especially cognitive behavioral psychotherapy

• Consider presence of concomitant substance abuse

• Consider presence of loflazepate abuse

• Consider another diagnosis, such as a comorbid medical condition

Best Augmenting Combos for Partial Response or Treatment Resistance

• Benzodiazepines are frequently used as augmenting agents for antipsychotics and mood stabilizers in the treatment of psychotic and bipolar disorders

• Benzodiazepines are frequently used as augmenting agents for SSRIs and SNRIs in the treatment of anxiety disorders

• Not generally rational to combine with other benzodiazepines

• Caution if using as an anxiolytic concomitantly with other sedative hypnotics for sleep

Tests

• In patients with seizure disorders, concomitant medical illness, and/or those with multiple concomitant long-term medications, periodic liver tests and blood counts may be prudent

LOFLAZEPATE: SIDE EFFECTS

How Drug Causes Side Effects

• Same mechanism for side effects as for therapeutic effects – namely due to excessive actions at benzodiazepine receptors

• Long-term adaptations in benzodiazepine receptors may explain the development of dependence, tolerance, and withdrawal

• Side effects are generally immediate, but immediate side effects often disappear in time

Notable Side Effects

✽ Sedation, fatigue, depression

✽ Dizziness, ataxia, slurred speech, weakness

✽ Forgetfulness, confusion

✽ Hyperexcitability, nervousness

• Rare hallucinations, mania

• Rare hypotension

• Hypersalivation, dry mouth

Life-Threatening or Dangerous Side Effects

• Respiratory depression, especially when taken with CNS depressants in overdose

• Rare hepatic dysfunction, renal dysfunction, blood dyscrasias

Weight Gain

• Reported but not expected

Sedation

• Occurs in significant minority

• Especially at initiation of treatment or when dose increases

• Tolerance often develops over time

What to Do About Side Effects

• Wait

• Wait

• Wait

• Lower the dose

• Take largest dose at bedtime to avoid sedative effects during the day

• Switch to another agent

• Administer flumazenil if side effects are severe or life-threatening

Best Augmenting Agents for Side Effects

• Many side effects cannot be improved with an augmenting agent

LOFLAZEPATE: DOSING AND USE

Usual Dosage Range

• 1 mg once or twice a day

Dosage Forms

• Tablet 1 mg, 2 mg

How to Dose

• Start at 1 mg, increase to 1 mg twice/day or 2 mg once a day in a few days if necessary

Dosing Tips

✽ Because of its long half-life, patients who require chronic treatment may need dose reduction after a few weeks due to drug accumulation

✽ Because of its long half-life, once daily dosing is the most frequent dosing generally necessary

✽ Because of its long half-life, some patients may have sustained benefits even if dosing is intermittently skipped on some days

• Use lowest possible effective dose for the shortest possible period of time (a benzodiazepine-sparing strategy)

• Assess need for continued treatment regularly

• Risk of dependence may increase with dose and duration of treatment

• For interdose symptoms of anxiety, can either increase dose or maintain same total daily dose but divide into more frequent doses

• Can also use an as-needed occasional “top up” dose for interdose anxiety

• Because panic disorder can require doses higher than 2 mg/day, the risk of dependence may be greater in these patients

• Some severely ill patients may require more than 2 mg/day

• Frequency of dosing in practice is often greater than predicted from half-life, as duration of biological activity is often shorter than pharmacokinetic terminal half-life, which is why once daily dosing is usually the favored option despite the long half-life

Overdose

• Sedation, confusion, poor coordination, diminished reflexes, coma

Long-Term Use

• Risk of dependence, particularly for treatment periods longer than 12 weeks and especially in patients with past or current polysubstance abuse

Habit Forming

• Patients may develop dependence and/or tolerance with long-term use

How to Stop

• Patients with history of seizures may seize upon withdrawal, especially if withdrawal is abrupt

• Taper by 0.5 mg every 3–7 days to reduce chances of withdrawal effects

• For difficult to taper cases, consider reducing dose much more slowly after reaching 3 mg/day, perhaps by as little as 0.25 mg every 7–10 days or slower

• For other patients with severe problems discontinuing a benzodiazepine, dosing may need to be tapered over many months (i.e., reduce dose by 1% every 3 days by crushing tablet and suspending or dissolving in 100 mL of fruit juice and then disposing of 1 mL while drinking the rest; 3–7 days later, dispose of 2 mL, and so on). This is both a form of very slow biological tapering and a form of behavioral desensitization

• Be sure to differentiate reemergence of symptoms requiring reinstitution of treatment from withdrawal symptoms

• Benzodiazepine-dependent anxiety patients and insulin-dependent diabetics are not addicted to their medications. When benzodiazepine-dependent patients stop their medication, disease symptoms can reemerge, disease symptoms can worsen (rebound), and/or withdrawal symptoms can emerge