What medications are contraindicated with olanzapine?

Medications Contraindicated or Requiring Caution with Olanzapine

There are no absolute contraindications listed in the FDA labeling for olanzapine, but several medications require significant caution due to serious drug interactions, particularly CNS depressants like benzodiazepines, alcohol, and other centrally-acting drugs. 1

High-Risk Combinations Requiring Dose Adjustment

Benzodiazepines (Especially Lorazepam and Diazepam)

• Concurrent use of olanzapine with benzodiazepines, particularly lorazepam (IM) and diazepam, significantly increases somnolence and risk of orthostatic hypotension. 1

• The ESMO guidelines specifically warn that fatalities have been reported with concurrent use of benzodiazepines with high-dose olanzapine, particularly noting the risk of oversedation and respiratory depression when combining olanzapine with benzodiazepines. 2

• When combining olanzapine with lorazepam, mandatory dose reduction to 0.25-0.5 mg of lorazepam is required, especially in elderly patients, those with COPD, or when co-administered with antipsychotics. 2

• Increased risk of respiratory depression, falls, and excessive sedation occurs with this combination, requiring careful monitoring of respiratory function and sedation levels. 2, 3

Alcohol

• Alcohol may potentiate orthostatic hypotension when combined with olanzapine and should be avoided due to additive CNS depression. 1

Medications Affecting Olanzapine Metabolism

CYP1A2 Inhibitors (Fluvoxamine)

• Fluvoxamine significantly increases olanzapine levels by 12-112% through CYP1A2 inhibition, requiring therapeutic drug monitoring to avoid olanzapine-induced side effects or intoxication. 1, 4

• This combination should be used cautiously with dose adjustments of olanzapine anticipated when fluvoxamine is added. 4, 5

• Hypersalivation has been reported as a paradoxical adverse effect when olanzapine is combined with fluvoxamine, despite olanzapine's typical anticholinergic effects. 5

CYP1A2 Inducers (Carbamazepine)

• Carbamazepine increases clearance of olanzapine, potentially reducing its efficacy and requiring higher olanzapine doses. 1

Medications with Additive or Antagonistic Effects

Antihypertensive Agents

• Olanzapine enhances the antihypertensive effect of blood pressure medications, increasing risk of orthostatic hypotension. 1

Levodopa and Dopamine Agonists

• Olanzapine may antagonize the effects of levodopa and dopamine agonists due to its dopamine receptor antagonism, potentially worsening Parkinson's disease symptoms. 1

Other CNS-Acting Drugs

• Caution is required when olanzapine is combined with any centrally-acting drugs due to additive CNS depression effects. 1

Anticholinergic Medications

• Use olanzapine with caution when combined with other anticholinergic drugs and in patients with urinary retention, prostatic hypertrophy, constipation, or paralytic ileus, as olanzapine has antimuscarinic effects. 1

Special Considerations for Combination Therapy

With Lithium or Valproate

• When using olanzapine with lithium or valproate, refer to the drug interaction sections of those products' package inserts for additional precautions. 1

With Fluoxetine

• When combining olanzapine with fluoxetine (as in Symbyax), refer to the specific package insert for that combination product regarding additional drug interactions. 1

Common Pitfalls to Avoid

• Do not use excessive dopamine blockade by combining olanzapine with metoclopramide, phenothiazines, or haloperidol, as this increases extrapyramidal symptoms risk. 2

• Elderly patients with dementia-related psychosis have increased mortality risk with olanzapine (FDA boxed warning), requiring extreme caution in this population. 2, 1

• Monitor for excessive sedation, falls, and respiratory depression when combining olanzapine with any CNS depressant, particularly in elderly or frail patients. 2, 3

• Therapeutic drug monitoring is essential when combining olanzapine with CYP1A2 inhibitors like fluvoxamine to prevent toxicity. 4