Nortriptyline and the Risk of Serious Adverse Events

Prior treatment

• Those with evidence of any study drug prescription 180 days before the index date (to restrict to new users only).
• Individuals with more than one study drug prescription on the index date, as this complicates the ability to ascertain the prescribed dose accurately.
• Evidence of other tricyclic antidepressants in the previous 180 days (including index date).
• Individuals with end-stage renal disease, chronic dialysis, or a kidney transplant prior to the index date.
• Evidence of a hospital discharge or emergency department visit in the two days prior to or on the index date to ensure a new outpatient prescription.

Lab values

• Individuals with no serum creatinine lab value in the 0-365 days prior to the index date.
• Individuals with unstable baseline kidney function:
  • If the most recent serum creatinine test prior to the index date was an inpatient test \[ER or hospitalization\] \<refer to this as test date 1\>, and there is not at least one outpatient serum creatinine in the year before test date 1, OR If the most recent prior serum creatinine test prior to the index date was an inpatient test \[ER or hospitalization\] \<refer to this as test date 1\>, and while there is at least 'outpatient' serum creatinine test in the year before \<test date 1\>, the most recent outpatient test prior to \<test date 1\> differs by an eGFR of 10 mL/min/1.73 m2 or more from the value on \<test date 1\>.
  • In Ontario, it has been shown that outpatient serum creatinine measurements in the province, conducted on a single occasion, indicate stable values.

Age

• Individuals with missing administrative database number, missing or invalid age (\<0 or \>105 years), missing or invalid sex, death on or before the index date, non-Ontario resident (for Ontario data), or non-Alberta residents (for Alberta data).
• Individuals less than 66 years of age on the index date.

Other

• Evidence of clinically non-meaningful nortriptyline doses (doses that are either too low or too high). The recommended nortriptyline dose range is 10 to 150 mg per day.
• The investigators restrict to the first prescription in individuals with more than one eligible prescription. The date of this prescription will be the index date (the date from which outcomes start being assessed).

• The cohort will include all older adults (≥66 years) with an eGFR \<45 mL/min per 1.73 m2 (not receiving dialysis or having a history of kidney transplantation) who received a new outpatient prescription for oral nortriptyline between January 1, 2008, and December 1, 2025.
  • The age criterion is set to guarantee that individuals in this population have had at least one year of prior prescription drug coverage. The date when the prescription was filled will serve as the patient's entry or index date for the cohort, with each patient entering the cohort only once.