PACE Case: Medication-Related Fall Risk, Smoking Cessation, and the Risk of Adverse Drug Events

A 59-year-old female PACE participant has a past medical history of major depressive disorder (MDD), gastroesophageal reflux disease (GERD), generalized chronic pain and fatigue, type 2 diabetes, diabetic polyneuropathy, vitamin D deficiency, insomnia, chronic obstructive pulmonary disease (COPD), and restless leg syndrome. The participant is a former smoker who is prescribed varenicline for smoking cessation therapy, and has a MedWise Risk Score™ of 29 out of 50 (high).

The participant’s current medication regimen includes:

• Albuterol sulfate, inhale 2 puffs PO 4 times daily, as needed for shortness of breath
• Atorvastatin 20mg, 1 tablet PO daily
• Cetirizine 10mg, 1 tablet PO daily
• Cholecalciferol 2000 intl units, 1 tablet PO daily
• Duloxetine 60mg, 2 capsules (120mg) PO daily
• Esomeprazole 20mg, 2 capsules (40mg) PO in the morning and 1 capsule (20mg) at bedtime
• Fluticasone/salmeterol 500-50mcg/dose, inhale 1 puff PO twice daily
• Furosemide 40mg, 1 tablet PO daily as needed for fluid retention
• Guaifenesin 600mg, 1 tablet PO every 12 hours as needed for congestion
• Ibuprofen 800mg, 1 tablet PO every 12 hours as needed for pain
• Ipratropium bromide/albuterol sulfate, inhale contents of 1 vial (3mL) via nebulizer 4 times daily, as needed for shortness of breath
• Melatonin 5mg, 1 tablet PO daily
• Montelukast 10mg, 1 tablet PO daily
• Oxybutynin 5mg, 1 tablet PO twice daily
• Polyethylene glycol 3350, mix 1 packet contents (17 grams) in 8 oz. of water and drink daily
• Potassium chloride 20mEq, 1 tablet PO daily
• Prednisone 20mg, 1 tablet PO daily
• Pregabalin 225mg, 1 capsule PO twice daily
• Propranolol 20mg, 1 tablet PO twice daily
• Ropinirole 1mg, 1 tablet PO daily
• Oxycodone 5mg twice daily as needed for pain
• Tiotropium 1.25mcg/actuation, Inhale 2 puffs PO daily
• Tizanidine 2mg, 1 tablet PO twice daily
• Varenicline 1mg, 1 tablet PO twice daily

The CareKinesis clinical pharmacist performed an assessment of the participant’s medication regimen for Fall Risk Increasing Drugs (FRIDs), and to identify medications that may require dosage adjustment or monitoring, given the participant recently quit smoking.

Participant Assessment:

• Smoking leads to induction of the CYP1A2 enzyme and lower concentrations of CYP1A2 substrates, such as duloxetine, tizanidine, and melatonin. With the participant’s smoking cessation, there would be lack of induction of the CYP1A2 enzyme, potentially increasing the concentrations of these substrates. This may lead to an increased risk of adverse drug events (ADEs), which may be mitigated by re-evaluating medication therapy and doses primarily metabolized by the CYP1A2 enzyme, as such:
  • The participant is prescribed duloxetine and pregabalin, both of which are used for neuropathic pain and anxiety; however, duloxetine also provides benefits for depression. Additionally, doses greater than 60mg daily of duloxetine have not been shown to be more effective and are associated with increased risk of ADEs, including orthostatic hypotension, which may contribute to falls. As a result, lower doses of duloxetine may be required to reduce the risk of ADEs.
  • The participant’s aggregate sedative burden score is 16, which is very high. Higher sedative burden scores are associated with frailty and lower objective physical function over time. Skeletal muscle relaxants have questionable efficacy, are recommended to be used short term, and with caution in older adults. The clearance of tizanidine may be decreased four-fold in older adults, thereby resulting in excess accumulation and increased potential ADE risk and duration of effects. Additionally, the concentration of tizanidine may be higher than expected when concomitantly administered with duloxetine, due to competitive inhibition of CYP1A2, which may further increase the risk of ADEs. Risk may outweigh benefit since tizanidine is associated with significant hypotension (16 to 33%), syncope, dizziness (16 to 45%), sedation (48 to 92%), visual hallucinations and nervousness (< 3%). As a result, a gradual dose reduction to potentially discontinue and lower doses of tizanidine may be required to reduce the risk of ADEs.
  • The participant is also prescribed melatonin for insomnia. Studies of melatonin for the treatment of insomnia have shown lower doses to be generally more efficacious; higher doses may cause morning grogginess without additional benefit. Additionally, the concentration of melatonin may be higher than expected when concomitantly administered with esomeprazole, since is a CYP2C19 inhibitor, which may further increase the risk of ADEs. As a result, lower doses of melatonin may be required to reduce the risk of ADEs and improve sleep.
• Older adults who are exposed to short-acting opioids, such as oxycodone, are at a significantly increased risk for falls due to impaired psychomotor skills. Additionally, oxycodone’s active metabolite may be lower than expected if concomitantly administered with duloxetine and propranolol due to competitive inhibition of CYP2D6. As a result, the participant may be at increased risk of therapeutic failure. Competitive inhibition of CYP3A4 with concomitant administration of atorvastatin, propranolol, and esomeprazole may also result in higher concentration of oxycodone, thereby further increasing the risk of ADEs related to toxicity.
• The participant is prescribed several medications, such as propranolol, duloxetine, oxybutynin, pregabalin, and tizanidine, which have a high incidence of dizziness and drowsiness. This combination of medications may have synergistic effects and may cause dizziness and orthostatic hypotension. In addition, if prescribed for blood pressure control, propranolol may not be the ideal choice of beta-blocker in older adults, given its central nervous system (CNS) penetration and nonselective action. Per the Eighth Joint National Committee (JNC8) guideline, a beta-blocker is not recommended as first-line therapy for hypertension without a compelling indication.
• The use of proton pump inhibitors (PPIs), such as esomeprazole, in older adults for more than eight weeks is not recommended given the increased risk of bone loss and osteoporotic fractures, along with clostridium difficile infections and gastritis. Because the participant is also taking ibuprofen and prednisone, the use of PPIs may be beneficial to reduce, but not eliminate, gastrointestinal bleeding. However, long-term use of NSAIDs increases the risk of gastrointestinal bleeding and peptic ulcer disease in older adults.
• The participant’s current COPD therapy consists of a long-acting muscarinic antagonist (LAMA) and inhaled corticosteroids (ICS)/long-acting beta2-adrenergic agonist (LABA) separately, along with oral prednisone 20mg daily. Chronic systemic corticosteroid use can increase the risk for osteoporosis, fractures, and impaired cognition. Additionally, the concentration of prednisone may be higher than expected if concomitantly administered with esomeprazole, atorvastatin, and propranolol due to competitive inhibition of CYP3A4. As a result, this may increase the risk of ADEs.

With the above assessment, the clinical pharmacist provided the following recommendations for prescriber consideration, as clinically appropriate, to reduce medication-related fall risk:

1. Re-evaluate dual therapy of pregabalin and duloxetine. Consider monotherapy therapy with duloxetine. Additionally, in consideration of smoking cessation and increased concentration, consider decreasing the duloxetine dose from 120mg to 60mg daily, to mitigate potential ADE risk with the current higher than recommended dose.
2. Re-evaluate continued use of tizanidine 2mg twice daily and consider a gradual dose reduction for possible discontinuation. A gradual taper is recommended to minimize the risk of withdrawal symptoms, such as rebound hypertension, tachycardia, and hypertonia. Consider alternative pain management depending on etiology and, if a muscle relaxant is deemed necessary, consider changing tizanidine to as needed, at the lowest effective dose, to mitigate the risk of potential ADEs.
3. To promote effectiveness and mitigate potential ADEs, decrease the melatonin dose from 5mg to 2mg. Counsel the participant to take one hour prior to bedtime. In addition, to mitigate the interaction with melatonin, de-escalate the PPI, esomeprazole, to an H2RA, such as famotidine 20mg daily. If a PPI is indicated, change to pantoprazole. Pantoprazole may be a safer alternative with fewer multi-drug interactions, as it does not undergo metabolism via CYP3A4, and is a weak CYP2C19 substrate.
4. Re-evaluate the benefits versus risks of continuing oxycodone 5mg twice daily as needed. If an opioid is indicated, separate the timing administration of oxycodone by at least two to four hours from competing medications (i.e. duloxetine and propranolol) and attempt a gradual dose reduction to prevent ADEs. If additional pain management therapy is indicated, depending on etiology and location of pain, consider topical analgesics such as diclofenac gel. To mitigate the interaction with oxycodone, switch atorvastatin 20mg to the equivalent moderate-intensity HMG-CoA reductase inhibitor, pravastatin 80mg, which is also associated with a lower risk of muscle weakness, since it is a hydrophilic rather than lipophilic statin.
5. Monitor propranolol for ADEs such as drowsiness, bradycardia, and confusion. If indicated for hypertension, consider an alternative such as lisinopril 5mg, if blood pressure allows, and adjust the dose as deemed appropriate.
6. Re-evaluate the benefits versus risks of continuing esomeprazole. If a PPI is indicated, consider switching to pantoprazole to mitigate drug interactions. Depending on the indication and frequency of use of ibuprofen, discontinue and consider topical NSAID, such as diclofenac, noted previously. If able to discontinue ibuprofen, consider a gradual taper of esomeprazole for possible discontinuation.
7. Re-evaluate the indication and benefits versus risks of long-term corticosteroid therapy with prednisone. If a corticosteroid is indicated, consider using the lowest effective dose for the shortest duration to reduce ADEs. Discontinue montelukast, since it does not currently have a place in COPD therapy, as per the GOLD guidelines. Additionally, it has a black box warning due to continued reports of neuropsychiatric events, such as sleeping problems, agitation, depression and suicidal thoughts and ideation. To optimize COPD management, consider a trial of triple therapy with Trelegy™ (ICS+LABA+LAMA), a once-daily inhaler to improve compliance and ease of administration, if the participant is experiencing frequent COPD exacerbations.

Conclusion:
While the clinical pharmacist’s recommendations were recently provided to the prescriber and awaiting clinical review and response, this case demonstrates the potential pharmacokinetic impact of smoking and the importance of re-evaluation of current therapies with smoking cessation. The clinical pharmacist identified several medications that may be impacted by smoking cessation and recommended that the prescriber adjust or monitor medications whose metabolism is affected by smoking cessation while also providing recommendations to mitigate medication-related fall risk.

If the prescriber is in agreement and it is clinically appropriate to make the recommended medication changes, the participant’s MedWise Risk Score™ of 29 (high) may be able to be reduced to as low as 18 out of 50, which is considered to be moderate. Further, aggregate sedative burden would be reduced from 16 to 9, further mitigating fall risk related to over sedation.

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