Does Ativan (lorazepam) interact with metronidazole or famotidine in patients with impaired renal function?

Ativan and Drug Interactions with Metronidazole and Famotidine

Ativan (lorazepam) does not have clinically significant pharmacokinetic interactions with either metronidazole or famotidine, but the combination with metronidazole carries important central nervous system (CNS) risks that require careful monitoring, particularly in patients with renal impairment.

Lorazepam and Famotidine: No Interaction

There is no clinically significant interaction between lorazepam and famotidine. 1, 2

• Famotidine demonstrates negligible interaction with hepatic cytochrome P450 enzymes and does not affect the metabolism of benzodiazepines like diazepam (a closely related benzodiazepine to lorazepam) 1, 2
• In controlled studies, therapeutic doses of famotidine did not impair diazepam clearance, elimination half-life, or total area under the curve, in direct contrast to cimetidine which significantly impaired benzodiazepine metabolism 1
• Famotidine can be safely coadministered with lorazepam without dose adjustment 2

Special Consideration in Renal Impairment

• Both lorazepam and famotidine require dose reduction in moderate to severe renal impairment (creatinine clearance <60 mL/min) 3, 4
• The American Geriatrics Society recommends using lower doses of lorazepam (0.25-0.5 mg) in older or frail patients, particularly those with chronic obstructive pulmonary disease (COPD) 3
• Famotidine clearance is substantially reduced in renal impairment, and CNS adverse reactions have been reported in elderly patients with renal dysfunction 4

Lorazepam and Metronidazole: Additive CNS Depression Risk

While there is no direct pharmacokinetic interaction between lorazepam and metronidazole, their combination significantly increases the risk of CNS toxicity, particularly CNS depression, confusion, and ataxia. 3, 5

Mechanism of Concern

• Metronidazole can cause CNS adverse effects including peripheral neuropathy, seizures, cerebellar ataxia, confusion, and encephalopathy, especially with prolonged use 5
• The 2019 American Geriatrics Society Beers Criteria specifically warns against concurrent use of three or more CNS-active agents (including benzodiazepines and antibiotics with CNS effects) due to increased fall risk and cognitive impairment 3
• Lorazepam itself can cause delirium, drowsiness, and paradoxical agitation 3

Clinical Implications

• Monitor closely for excessive sedation, confusion, ataxia, and respiratory depression when combining these agents 3
• Use the lowest effective dose of lorazepam (0.25-0.5 mg in older/frail patients) when metronidazole is necessary 3
• Consider alternative anxiolytics or sedatives with shorter half-lives if prolonged metronidazole therapy is required 3
• Metronidazole-induced CNS toxicity is more common with prolonged use (>2 weeks) and higher cumulative doses 5

Critical Warnings in Renal Impairment

In patients with impaired renal function, the combination of lorazepam and metronidazole requires extreme caution and dose reduction of both agents. 3, 4, 6

• Lorazepam should be used at reduced doses (0.25-0.5 mg) in renal impairment, and subcutaneous injection may cause local irritation 3
• Metronidazole plasma clearance is decreased in patients with decreased liver function, and elderly patients may require serum level monitoring 6
• The risk of CNS adverse effects from both drugs is substantially higher in elderly patients with renal impairment 3, 4
• Famotidine is known to be substantially excreted by the kidney, and the risk of adverse reactions may be greater in elderly patients with impaired renal function 4

Practical Management Algorithm

For Patients with Normal Renal Function:

• Lorazepam + Famotidine: Use standard doses without adjustment 1, 2
• Lorazepam + Metronidazole: Use with caution; monitor for excessive sedation, confusion, and ataxia 3, 5

For Patients with Renal Impairment (CrCl <60 mL/min):

• Reduce lorazepam dose to 0.25-0.5 mg 3
• Reduce famotidine dose per manufacturer recommendations 4
• Monitor metronidazole serum levels if available and consider dose adjustment 6
• Avoid combining all three agents if possible 3
• Assess for signs of CNS toxicity at each clinical encounter 3, 4

Common Pitfalls to Avoid:

• Do not assume all H2-receptor antagonists interact similarly with benzodiazepines—famotidine is distinctly different from cimetidine 1, 2
• Do not overlook the additive CNS depression risk when combining lorazepam with metronidazole, even in the absence of direct pharmacokinetic interaction 3, 5
• Do not use standard doses of lorazepam or famotidine in elderly patients with renal impairment without dose reduction 3, 4
• Be aware that metronidazole CNS toxicity can occur even with short-term use in susceptible patients 5