PACE Case: Avoiding Competitive Inhibition and Evaluating Therapeutic Benefits in Older Adults

Challenge

EM is an 87-year-old male with a past medical history of hypertension, dyslipidemia, congestive heart failure (CHF), type 2 diabetes, dementia, major depressive disorder, gastro-esophageal reflux disease (GERD), constipation, cerebrovascular and peripheral vascular disease, sleep apnea, chronic obstructive pulmonary disorder (COPD), and benign prostatic hyperplasia (BPH) with lower urinary tract symptoms. EM’s MedWise Risk Score™ is 24 (high risk).

24 out of 50 risk score
The participant’s medication regimen includes:

  • Amlodipine 10mg daily
  • Atorvastatin 20mg daily
  • Clonidine 0.2mg daily
  • Docusate 100mg daily
  • Hydralazine 50mg, four times daily
  • Memantine XR 7mg daily
  • Metoprolol tartrate 50mg twice daily
  • Olanzapine 5mg twice daily
  • Pantoprazole 40mg daily
  • Quetiapine 100mg daily at bedtime

During a polypharmacy call with the PACE prescriber, the following medication-related problems were identified by the CareKinesis clinical pharmacist:

  • The participant is currently taking both his atorvastatin and quetiapine at bedtime. These two substrates are metabolized by the same cytochrome P450 isoenzyme, namely CYP3A4. The stronger substrate, atorvastatin, demonstrates greater affinity for CYP3A4. As a result, we should expect to observe greater concentrations of the weaker substrate, quetiapine. This may potentially increase the risk of adverse effects associated with quetiapine, such as anticholinergic side effects, dizziness, and drowsiness.
  • The participant is currently taking memantine XR 7mg daily. This low dose of memantine may be considered sub-therapeutic and not provide therapeutic benefits.
  • The participant takes metoprolol tartrate 50mg twice daily, which may contribute to his total daily pill burden. Additionally, studies have shown that the succinate formulation provides substantial mortality and morbidity benefits in heart failure. His blood pressure and heart rate is stable and at goal.
  • The participant is currently taking pantoprazole 40mg daily. Long-term proton pump inhibitor (PPI) therapy has been associated with increased osteoporosis-related fracture risk since decreases bone density, along with electrolyte imbalances, such as hypomagnesemia, vitamin B12 malabsorption and subsequent B12 deficiency (possible neuropathy), clostridium difficile infection, and gastritis.
  • The participant is currently taking quetiapine 100mg at bedtime. Antipsychotic use in patients with Behavioral and Psychological Symptoms of Dementia (BPSD) is not recommended due to an associated increase in mortality risk related to cardiovascular and infectious complications. Quetiapine is highly anticholinergic, and therefore also associated with potential adverse central nervous system effects, metabolic risks, and increased risk of falls. At lower doses, quetiapine acts on alpha-1 and histamine receptors, which may cause sedation. Current evidence also suggests that quetiapine is ineffective for the treatment of insomnia.

Solution

The following recommendations were discussed with the PACE prescriber to mitigate multi-drug interactions and revisit pharmacological treatment indication and efficacy:

  • If concurrent therapy with atorvastatin and quetiapine is necessary, consider changing the time of administration of atorvastatin from the evening to the morning. Atorvastatin is a long-acting statin and can be dosed at any time of the day. Separating the times of administration between atorvastatin and quetiapine will mitigate the risk of increased concentrations of quetiapine and associated side effects.
  • Re-evaluate the benefit versus risk of therapy taking into consideration goals of care. If therapy is indicated to continue and tolerating well with no GI adverse effects, consider increasing the memantine XR dose by 7mg every week, as tolerated, to the targeted maximum dose of 28mg daily. Continue to monitor the participant closely for therapeutic efficacy with memantine.
  • Metoprolol succinate has benefits of once-daily dosing and mortality benefit in heart failure. Consider changing metoprolol tartrate 50mg twice daily to the equivalent, metoprolol succinate ER 100mg daily.
  • Consider tapering the dose of pantoprazole with the goal of discontinuation. If acid-suppression therapy is still indicated, an H2-receptor antagonist (H2RA), such as famotidine 10mg daily, would be a preferred alternative.
  • Evaluate the indication for quetiapine therapy and its effectiveness. Quetiapine is not recommended for the treatment of insomnia and it is not recommended for chronic use in patients with dementia. If the indication is insomnia, consider safer alternatives such as melatonin or trazodone. If the indication is BPSD, and an antipsychotic is clinically indicated, consider risperidone as a preferred alternative.

Benefit/Outcome

  • The PACE prescriber agreed that separating the times of administration of atorvastatin and quetiapine would benefit the participant, as it would mitigate the competitive inhibition interaction causing increased concentrations of quetiapine. The CareKinesis clinical pharmacist changed the scheduled time of administration of atorvastatin to morning, per collaborative agreement.
  • Because the participant was recently initiated on memantine, the prescriber made note of the risk of therapeutic failure with low-dose therapy. The prescriber agreed to closely monitor the progression of the participant’s dementia and adjust the dosage depending on his response to memantine treatment.
  • The prescriber agreed to switch metoprolol tartrate to metoprolol succinate formulation to provide additional mortality benefit for the participant. As metoprolol succinate has the benefit of once-daily dosing, this also reduces pill burden.
  • The prescriber decided that the participant could be tapered off pantoprazole therapy and switched to famotidine, in consideration of long-term risks with PPI use. The prescriber acknowledged that quetiapine is not recommended for the treatment of insomnia and agreed to trial a gradual dose reduction to potentially discontinue therapy. Olanzapine is to continue at this time.

Conclusions/Lessons Learned

By addressing the dual antipsychotic therapy with the gradual taper and discontinuation of quetiapine, along with the additional medication changes made, the participant’s MedWise Risk Score was reduced to 17 (moderate-risk).

17 out of 50 moderate risk score

Changing the time of administration of atorvastatin to the morning and switching from a PPI to an H2RA mitigates the potential ADE risk with quetiapine, as therapy is gradually tapered, and pantoprazole. Further, changing metoprolol tartrate to metoprolol succinate formulation optimizes the participant’s CHF management for proven morbidity and mortality benefit.

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