PACE CASE: Unexplained Fatigue

An 86-year-old male PACE participant with a history of diabetes, high cholesterol, hypertension, surgically debrided diabetic foot ulcers, Methicillin-resistant Staphylococcus aureus (MRSA), and iron deficiency anemia complained of constant fatigue. The medical director suspected that the participant’s meatless diet was partially to blame for the fatigue and asked the CareKinesis clinical pharmacist to perform a Comprehensive Medication Review (CMR) to rule out medications as the cause.

Participant’s full medication list:
Vytorin 10 mg-40 mg 1 tab daily to reduce cholesterol
Omega-3 fish Oil 1200 mg 1 cap daily to reduce triglycerides
Januvia 100 mg 1 tab daily to reduce blood sugar
Invokana 100 mg 1 tab daily to reduce blood sugar
Glyburide/Metformin 5 mg-500 mg 1 tab daily to reduce blood sugar
Nitroglycerin 0.4 mg sublingual 1 tab under tongue as needed for chest pain
Clopidogrel 75 mg 1 tab daily to reduce clotting, improve circulation
Metoprolol Tartate 25 mg 1 tab daily for heart, blood pressure control
Valsartan 160 mg 1 tab daily for heart, blood pressure control
Aspirin 81 mg 1 tab daily to reduce clotting, improve circulation
Doxycycline HCl 100 mg 1 cap daily for infection
iron 65 mg 1 tab daily as supplement for anemia
CoQ10 100 mg 1 cap daily as a supplement
Citracal 500/400 + D 1 tab daily as a calcium supplement
Vitamin B-12 1000 mcg 1 tab daily as a supplement
Finasteride  5mg 1 tab daily for prostate, to improve urine flow
Flomax 0.4 mg 1 cap daily for prostate, to improve urine flow
Hydrochlorothiazide 25 mg 1 tab daily to reduce fluid, swelling
Latanoprost 0.005% ophthalmic soln 1 drop in both eyes to reduce eye pressure
Probiotic formula 1 cap daily

After reviewing the medication list, the clinical pharmacist contacted the participant for more information about exactly how he was taking his medications. During this conversation, the participant shared that he was taking all of his pills together, once daily, in the morning. He reported some lab values that had not yet been communicated to the pharmacy. The participant also shared that he has been a vegetarian for more than five years.

The clinical pharmacist completed the interview, and submitted the following CMR recommendations to the PACE medical director. As part of the new plan, the pharmacist recommended separate administration times of the participant’s calcium, doxycycline, and iron as when taken together, forms a complex which may impair intestinal absorption.


The simple change of taking his calcium, doxycline, and iron seperately enabled much greater absorption of the iron, which significantly improved his anemic status and helped alleviate his fatigue symptoms. In addition, the enhanced absorption of the antibiotic led to improved healing of his foot wound.

Recommendation Detail
Possible unnecessary therapy: ezetimbe


Evaluate for discontinuation

Patricipant self-reports excellent lab values associated with hypercholesterolemia (very low total cholesterol, LDL, and triglycerides). Ezetimibe, an ingredient in Vytorin®, is an inhibitor of dietary cholesterol absorption via the intestines. Participant is a self-reported vegetarian. Unless he eats an abundance of cheese or dairy products that are high in saturated fats or cholesterol (“Vegan” vs. “Vegetarian”), he may not be getting much benefit from this medication vs. a statin alone while increasing his risks of muscle pain, weakness, liver enzyme elevations, etc. Based upon lab values and physical assessment, you may wish to consider discontinuation.
Possible ineffective (or marginally effective) therapy: Januvia®


Evaluate for discontinuation

Participant self-reports excellent lab values associated with his type 2 diabetes (very good FBS and HGB A1c). In clinical trials, Januvia® reduced A1c only 0.65% when compared to placebo (~ 0.2 points). Depending on when/why Januvia was added to the participant’s therapy, you may wish to consider discontinuation.
Possible ADR: Drug-Drug Interaction


Continue meds, monitor labs closely

Invokana® works by increasing the urinary excretion of glucose. This enhanced diuresis may result in increased sodium excretion; taken with Valsartan it can result in hyperkalemia (patient self-reports a potassium level of 5.3). While only a modest increase in level, the trend could be a result of this drug/drug interaction, dietary ingestion of fruits/vegetables high in potassium or reduced renal function secondary to age, HTN, DM, etc. Please continue to monitor these closely.
Possible ADR: Drug-Disease Interaction


Monitor signs closely, evaluate for discontinuation

Invokana® contains within its prescribing information increased risks for:

  • Lower limb amputations with: h/o heart disease, peripheral circulation problems or diabetic foot ulcers (all of which the patient reports having)
  • Dehydration
  • Renal insufficiency with hyperkalemia
  • Increased fracture risk
Possible ADR: Drug-Genetic Interaction


Consider Phamacogenomic test (CYP enzyme 2C19)


  • Responsible for primary activation of Plavix® to active metabolite responsible for anti-platelet activity. If participant carries a *17 allele, he is at increased risk for bleeding (participant self-reports large purple bruises and anemia with low hemoglobin and hematocrit – levels were not available when asked). If this is the case, Plavix® should be discontinued in favor of another medication (e.g., prasugrel, Effient®, ticagrelor, Brilinta®) or aspirin therapy alone (no greater than 81 mg/day as ZM is > 80 yo)
Recommended dosing in renal impairment


Monitor labs / diagnostic tests

Metformin: Per current ADA guidelines,

  • Continue Metformin if GFR > 45
  • Monitor risks vs benefits if GFR > 30 and < 45
  • Discontinue if GFR < 30
Medication Counseling Participant self-reports that he takes all medications in the morning. I recommend that he increase to 2 administration times each day.

Six of the participant’s medications are competing for the same enzymes necessary for metabolism (CYP 3A4), and this enzyme congestion can lead to buildup and toxicity. Separation of administration can facilitate proper metabolism.

Calcium, iron, and doxycycline need to be separated, as they all impair the gut absorption of each other.

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