Is it appropriate to give 1 mg clonazepam at bedtime, 45 mg flurazepam at bedtime, and 20 mg olanzapine (Zyprexa) at bedtime?

Polypharmacy with Multiple Sedating Agents at Bedtime: Safety and Appropriateness

This combination of 1 mg clonazepam, 45 mg flurazepam, and 20 mg olanzapine all at bedtime is NOT appropriate and represents dangerous polypharmacy that significantly increases risks of respiratory depression, falls, cognitive impairment, and death—particularly in elderly patients. 1

Critical Safety Concerns

Respiratory Depression Risk

• Combining two benzodiazepines (clonazepam and flurazepam) with a sedating antipsychotic (olanzapine) creates compounding respiratory depression risk, especially when combined with opioids or alcohol, with documented fatal outcomes. 1
• Benzodiazepines should be avoided entirely in patients with severe pulmonary insufficiency due to high risk of adverse outcomes. 1
• Clonazepam at 0.5-1.0 mg can worsen or precipitate sleep apnea, and this risk is magnified when combined with another benzodiazepine. 2

Redundant Benzodiazepine Use

• There is no clinical rationale for combining two long-acting benzodiazepines (clonazepam half-life 30-40 hours; flurazepam with active metabolites extending 50-95 hours). 1
• This combination creates excessive GABA-A receptor potentiation leading to prolonged sedation, cognitive impairment, falls, and respiratory depression. 1
• Both agents have overlapping mechanisms and clinical effects, making dual therapy pharmacologically redundant. 1, 3

Excessive Olanzapine Dosing

• The 20 mg olanzapine dose is at the upper limit of FDA-approved dosing and should not be combined with dual benzodiazepines for sleep. 4
• The American Academy of Sleep Medicine explicitly recommends against using atypical antipsychotics like olanzapine for primary insomnia due to weak efficacy evidence and significant side effects including weight gain, dysmetabolism, and neurological effects. 5
• Olanzapine carries an FDA black box warning for increased mortality risk in elderly patients with dementia-related psychosis. 5

Special Population Risks

• In elderly patients, clonazepam appears on the American Geriatrics Society Beers Criteria as potentially inappropriate due to heightened risks of sedation, falls, confusion, and cognitive impairment. 1
• The American Geriatrics Society recommends reducing benzodiazepine doses by 20% or more in patients over 60 years due to decreased clearance and accumulation. 1
• Common side effects of clonazepam include morning sedation, confusion, memory dysfunction, early morning motor incoordination, and falls with potential for subdural hematoma at 2.0 mg doses. 2
• A recent retrospective study found 58% of patients on clonazepam for REM sleep behavior disorder experienced moderate or severe side effects, with 13 of 36 patients discontinuing the medication. 2

Appropriate Clinical Approach

For Primary Insomnia

• First-line treatment should be short-intermediate acting benzodiazepine receptor agonists (zolpidem, eszopiclone, zaleplon, temazepam) or ramelteon as monotherapy, not combination therapy. 5
• Cognitive behavioral therapy for insomnia (CBT-I) should be considered as first-line non-pharmacological treatment. 5
• If a benzodiazepine is used, select ONE agent: temazepam, loprazolam, or lormetazepam with medium duration of action are suitable for short-term use (ideally maximum 2-4 weeks). 3

For REM Sleep Behavior Disorder

• Clonazepam monotherapy at 0.5-1 mg at bedtime is the most effective treatment, with 90% efficacy. 2
• Melatonin 3-12 mg at bedtime is recommended as a safer alternative, especially in patients with dementia, sleep-disordered breathing, or elevated fall risk where benzodiazepines are contraindicated. 2, 1
• There is no indication for adding flurazepam or olanzapine to clonazepam for RBD. 2

Contraindications to Consider

• Clonazepam should be used with caution in patients with neurodegenerative disorders, obstructive sleep apnea, and underlying liver disease. 2
• All benzodiazepines increase respiratory depression risk in obstructive sleep apnea; extreme caution or avoidance is warranted. 1

Common Pitfalls to Avoid

• Never combine multiple benzodiazepines without clear, distinct clinical indications (e.g., one for seizures, one for panic disorder—but even this requires careful justification). 1, 3
• Avoid prescribing benzodiazepines for longer than 2-4 weeks for insomnia to prevent tolerance, dependence, and withdrawal effects. 3
• Do not add sedating antipsychotics to benzodiazepines for primary insomnia—this is off-label use with poor evidence and significant harm potential. 5
• Monitor closely for orthostatic hypotension, sedation, and dizziness when any of these agents are used, and ensure adequate hydration. 5