What is the recommended dosing strategy for mirtazepine in elderly patients, particularly those with impaired renal (kidney) function or liver function?

Mirtazapine Dosing in the Elderly

Start mirtazapine at 7.5-15 mg once daily at bedtime in elderly patients, with conservative dose titration and mandatory dose reduction in those with moderate to severe renal or hepatic impairment. 1

Initial Dosing Strategy

• Begin with 7.5-15 mg once daily at bedtime in elderly patients, using the lower end of the dosing range due to decreased clearance and increased sensitivity in this population 1
• The FDA label explicitly states that "dose selection for an elderly patient should be conservative, usually starting at the low end of the dosing range" 1
• Pharmacokinetic studies demonstrate that elderly patients show higher plasma concentrations than younger adults due to decreased clearance of mirtazapine 1, 2

Dose Titration

• After 4-7 days at the starting dose, increase to 15 mg once daily if tolerated 2, 3
• If response is insufficient after 10-14 days at 15 mg, may increase to 30 mg once daily 3
• Maximum dose of 45 mg/day may be considered only in patients who demonstrate inadequate response at lower doses and tolerate the medication well 3, 4
• Allow 4-6 days to reach steady-state concentrations in elderly patients (longer than the 4 days typical in younger adults) 2, 5

Renal Impairment Adjustments

Mirtazapine is 75% renally excreted, making dose adjustment critical in renal dysfunction 1

• Moderate renal impairment (CrCl 30-60 mL/min): Reduce dose by approximately 30%; start with 7.5 mg once daily 1, 2
• Severe renal impairment (CrCl <30 mL/min): Reduce dose by 50%; start with 7.5 mg every other day or 7.5 mg once daily with extended titration intervals 1, 2
• The FDA label states that "dosage decrease may be necessary when administering mirtazapine tablets to patients with moderate to severe renal impairment" 1

Hepatic Impairment Adjustments

• Moderate to severe hepatic impairment: Reduce dose by approximately 30%; start with 7.5 mg once daily 1, 2
• Mirtazapine undergoes extensive hepatic first-pass metabolism (approximately 50% bioavailability), making hepatic function critical to clearance 2, 6
• The clearance of mirtazapine is reduced by about 30% in patients with hepatic impairment compared to those with normal liver function 1, 2

Critical Safety Monitoring in the Elderly

Elderly patients face heightened risks of sedation, confusion, falls, and hyponatremia with mirtazapine 1

• Monitor for excessive sedation and confusion, as sedating drugs including mirtazapine "may cause confusion and over-sedation in the elderly" 1
• Assess for orthostatic hypotension and fall risk at each visit, particularly during dose titration 1
• Monitor serum sodium levels, as elderly patients are at greater risk of developing hyponatremia 1
• Evaluate for weight gain and increased appetite, which occur in approximately 10% of patients (vs 1% with placebo) 3, 4

Common Pitfalls to Avoid

• Do not start at standard adult doses (15-30 mg) in elderly patients, as this increases risk of excessive sedation and falls 1
• Do not overlook renal function assessment before initiating therapy, as 75% of the drug is renally excreted 1
• Do not assume sedation will resolve with continued dosing in elderly patients; if problematic sedation occurs, reduce the dose rather than waiting for tolerance 1, 4
• Do not combine with other sedating medications (benzodiazepines, opioids, antipsychotics) without careful monitoring, as this substantially increases risk of over-sedation and respiratory depression 7

Pharmacokinetic Considerations

• Elimination half-life ranges from 20-40 hours, supporting once-daily dosing at bedtime 2, 6, 5
• The drug is metabolized primarily by CYP2D6, CYP3A4, and CYP1A2 2, 5
• Plasma concentrations are typically 5-100 mcg/L with therapeutic doses of 15-45 mg/day 2
• Gender differences exist, with females showing higher plasma concentrations than males at equivalent doses 2