Proper timing of medication administration can maximize effectiveness, minimize adverse effects, optimize adherence, and prevent unnecessary polypharmacy. This is because drug-food interactions and medication temporal patterns can have substantial effects on patient outcomes. This article examines some commonly used medications that are prone to improper administration and outlines solutions for addressing these challenges. Consideration should also be given to clinical judgment, consistency, and individualization of drug therapy to patient and caregiver needs beyond the general recommendations found in this article.
Case presentation
Anna, a frail 81-year-old woman, is new to your practice after another family doctor in your area retired. Anna has multiple medical conditions including hypertension, nonvalvular atrial fibrillation (for about 1 year), diabetes, hypothyroidism, and osteoporosis. She was diagnosed with Alzheimer disease by your colleague approximately 1 year ago and began treatment for iron deficiency anemia 3 months ago. Anna also has a long list of medications (Table 1).
At Anna’s second appointment with you she is accompanied by her daughter Jane. Anna lives with Jane and relies on her for assistance with instrumental activities of daily living, as well as bathing and dressing. They would prefer that Anna continue living at home for as long as she can. Jane manages Anna’s medications by filling a dosette box for her and reminding her to take them, proudly stating that Anna “never misses a dose.” However, Jane has some concerns about Anna’s health: she is often tired during the day but wanders in the night, and she has pedal edema, which makes wearing shoes uncomfortable. Anna previously wore compression stockings but has been resistant to this lately because donning them is difficult.
During Anna’s last appointment (1 month ago), you decided not to make changes to her medications but sent her for bloodwork. You also requested that her pharmacy perform a full medication review, including details on the time of day that medications are given, administration with food, and any over-the-counter medications not on your file. Table 1 and Box 1 show her current medication regimen, bloodwork, and vital signs. As you review her medications, you identify several potential issues.
Anna’s detailed medication history
Anna’s medical history
Recent bloodwork
Results
eGFR=69 mL/min
Serum creatinine=71 μmol/L
Levels within normal limits
TSH=0.87 mIU/L
T4=16 pmol/L
Electrolytes
Calcium
Lipid panel
Abnormal levels
Increased HbA1c=8.4% (3 mo ago=8.9%)
Decreased Hb=103 g/L
Decreased iron=5.4 μmol/L
Decreased TIBC=49 μmol/L
Decreased TSAT=11%
Decreased ferritin=13 μg/L
Decreased MCV=76.8 fL
Physical examination
Findings on presentation
Blood pressure=132/84 mm Hg
Heart rate=74 beats/min
No shortness of breath
2+ pitting edema
MMSE=20/30 (vs 23 upon dementia diagnosis)
Previous chart history findings
Echocardiogram 2 y ago, LVEF=59%
Intolerance to sulfonylureas
eGFR—estimated glomerular filtration rate, Hb—hemoglobin, HbA1c—hemoglobin A1c, LVEF—left ventricular ejection fraction, MCV—mean corpuscular volume, MMSE—Mini-Mental State Examination, T4—thyroxine, TIBC—total iron bonding capacity, TSAT—transferrin saturation, TSH—thyroid-stimulating hormone.
Timing medications with food
Some medications have increased absorption and effectiveness when taken with food (eg, nitrofurantoin,1 metformin extended release [XR],2 and rivaroxaban doses ≥15 mg).3,4 Food can also be a useful tool for improving tolerability and reducing the gastrointestinal side effects of many drugs (including metformin, prednisone, iron supplements, and nonsteroidal anti-inflammatory drugs).5,6 However, some medications have substantially decreased absorption in the presence of food (eg, bisphosphonates,7 levothyroxine,8 iron supplements,9 and cloxacillin10), which reduces clinical effect. Table 2 describes the change in bio-availability (extent of absorption) among selected medications when taken with food compared with an empty stomach.7,11-32
Bioavailability of common medications when taken with or without food
Anna is taking several medications that are time sensitive with regard to meals. Her metformin XR is both better absorbed (increases by 50%) and better tolerated if taken with food.17,18 Her dose of rivaroxaban is recommended by guidelines33 and product manufacturers3 to be taken with a meal to increase bioavailability (from 66% to 80% up to 100%) and thus avoid inadequate anticoagulation that may occur under fasting conditions (note that rivaroxaban doses of ≤10 mg have high absorption regardless of food intake).19-21 Her weekly alendronate should not be taken with breakfast since this decreases absorption by 85% to 90%, rendering it ineffective.7,11 Only bisphosphonates that are delayed release (DR) can be taken after food (eg, risedronate DR).34 Although Anna’s levothyroxine has reduced bioavailability when taken with food (decreased by about 15%),8,16,35 the dose can be titrated to target thyroid-stimulating hormone (TSH) and thyroxine (T4) levels. Thus, consistency with levothyroxine administration is most important. In this case, because Anna’s TSH and T4 levels are within normal limits, the timing of levothyroxine does not necessarily have to be changed.
In summary, it is important that Anna take her metformin XR–sitagliptin combination and rivaroxaban with sizable meals; her alendronate with a glass of water and without food or other medications; and her levothyroxine consistently either with or without food.
Important drug-mineral interactions
Chelating medications must be properly spaced from minerals. When polyvalent cations (calcium, magnesium, aluminum, or iron) are administered with certain drugs (such as ciprofloxacin or tetracycline), the formation of an insoluble “chelate” complex can prevent absorption.36,37 Table 3 lists some common chelating medications and how to time their administration (typically about 2 hours before or roughly 4 hours after minerals).7,35,38-44 Of note, many polyvalent cations are found in food (eg, calcium in milk) and in over-the-counter products (eg, multivitamins, antacids), which can inadvertently create drug interactions. Minerals can also negatively affect each other: for example, calcium can reduce iron absorption.25,45 Switching calcium supplements to dietary sources while decreasing product interactions may be preferred by guidelines (as long as dairy is not taken with chelating medications).46 Since chelation and intestinal interactions can drastically decrease bioavailability—sometimes by more than 90%—identification of these problems and subsequent separation is necessary to maximize effectiveness.47
Chelating medications and cation administration times: Cations include calcium, magnesium, aluminum, and iron.
Anna has prescriptions for 2 chelating medications (levothyroxine and alendronate) and 1 polyvalent cation (calcium carbonate). Anna will not adequately absorb her alendronate if it is not spaced apart from her calcium supplement as well as dietary interactions. Her levothyroxine does not necessarily require separation if her thyroid test results remain stable.
Medications at the optimal time of day
Chronotherapeutics refers to timing medical treatment based on circadian rhythms to increase the effectiveness of medications or to minimize adverse effects.48,49 Evidence in this field of medicine is emerging but sometimes conflicting.
Dihydropyridine calcium channel blockers. These, such as amlodipine and nifedipine, can induce pedal edema. Strategies to minimize this side effect include lowering the dose, switching to a different drug, combining with an angiotensin-converting enzyme inhibitor,50 or administering at bedtime. A randomized study involving nifedipine XR showed edema rates of 13.4% when nifedipine was administered in the morning compared with 1% in the evening.51 Since leg elevation (eg, lying with a pillow under the legs) can reduce edema by shifting fluid back to the heart,52,53 timing peak drug levels at night may lessen daytime symptoms. Chronotherapeutic studies have yet to be conducted on other dihydropyridine calcium channel blockers in this context.
Stimulating medications. These medications, such as bupropion, methylphenidate, and steroids, are best taken in the morning to prevent sleep disturbances, while sedating medications (such as fluvoxamine, amitriptyline, and olanzapine) should be taken in the evening to avoid daytime drowsiness.54,55,56 Although originally recommended by the manufacturer to be taken in the evening,57 donepezil can be taken in the morning.58 A small trial of 54 patients taking donepezil showed that those who were randomized to take donepezil in the evening had worse sleep outcomes than those in the morning group.59
Antihypertensive medications. The timing of antihypertensive medications is contentious. Evidence from clinical trials showed absolute risk reductions in cardiovascular events of 11% and 5.4%, respectively, when antihypertensives were taken at bedtime compared with the morning.60,61 However, methodologic issues make this evidence uncertain.62 More recently, a 5-year study revealed no difference in risk of cardiovascular events between bedtime and morning administration (3.4% vs 3.7%, hazard ratio=0.95).63 Upcoming results of a Canadian trial will shed additional light on the subject.64 Prioritizing adherence by giving antihypertensives at the most convenient time of day for patients is likely best.
Statins. Statins are conventionally taken at bedtime since cholesterol synthesis peaks then, but this is not always required. Long-acting statins (atorvastatin, rosuvastatin, and fluvastatin XR) can be taken at any time of day without consequence. Short-acting statins (fluvastatin, lovastatin, pravastatin, and simvastatin) have half-lives of 6 hours or less and may be best taken at night for maximum low-density lipoprotein reduction.65,66 Of note, hard outcomes such as cardiovascular events and mortality have not yet been examined in relation to timing.
Anna’s donepezil can be stimulating and is best taken in the morning to minimize sleep disturbances. Her amlodipine could be trialed at bedtime to see if this reduces her leg swelling and increases the antihypertensive effect, although data to support this approach are limited. Evidence suggests Anna’s atorvastatin can be taken at any time of day (although if she were taking a short-acting agent such as simvastatin, bedtime administration might be best).
Case resolution
After analyzing Anna’s bloodwork, evaluating medication administration patterns, and consulting with Jane and Anna, you recommend the following:
Switch donepezil from evening to morning administration to attempt to improve Anna’s sleep.
Have Anna take her weekly alendronate as soon as she wakes up, with plain water, at least 30 minutes before breakfast and other medications to maximize absorption. Alternatively, a switch could be made to risedronate DR to allow for administration with a meal and other medications, but this formulation is not covered by government drug benefit plans in most Canadian provinces and may cost Anna about $15 more per month.
Move rivaroxaban administration from bedtime to suppertime (her largest meal) to maximize absorption and thus maximize stroke prevention.
Move Anna’s metformin XR and sitagliptin to suppertime (her largest meal) to maximize absorption.
Administer amlodipine at supper in the hope of improving her pedal edema. Alternatively, adding an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker might help.50
Move calcium carbonate to suppertime to avoid interactions with alendronate and levothyroxine. Alternatively, consideration may be given to stopping Anna’s calcium supplement and encouraging dietary calcium sources (which would still require spacing from alendronate and levothyroxine).
Continue levothyroxine at breakfast, since Anna’s thyroid function test results are within range. However, you reorder thyroid function tests for 6 weeks from now, since you suspect Anna’s levothyroxine dose may have to be adjusted after removal of the calcium drug interaction.
Since you are substantially changing Anna’s medication routine, you also recommend that her pharmacy place her medications in blister packs.
Conclusion
Hidden interactions—both helpful and harmful—can impact drug absorption, so it is important to properly space medications to avoid interference from chelates and to note when administration with or without food may be necessary. Similarly, taking medications at the wrong time of day can result in unwanted side effects or hinder therapeutic effect. When managing medical conditions that can be reactively dose adjusted based on laboratory results (eg, TSH and T4 levels, international normalized ratio, and cholesterol levels), consistency in medication administration is usually the top priority. However, optimal administration time is most essential when the effectiveness of medications, like bisphosphonates, cannot be readily monitored. By analyzing an existing medication regimen before adding new drugs, the harms associated with polypharmacy and prescribing cascades can be reduced.
In Anna’s case, her medication schedule changed to 3 times per day. This type of schedule may not be manageable for every patient. When caregiver support for “perfect” medication timing is limited, alternative medications may need to be chosen (or new therapeutic goals set). Providers can find the balance between optimal medication timing and a schedule that works for patients and caregivers.
Acknowledgment
We thank Loren Regier and Brent Jensen for review of the manuscript.
Footnotes
Competing interests
The RxFiles Academic Detailing Program is funded through a grant from the Saskatchewan Health Authority to the University of Saskatchewan; additional “not for profit; not for loss” revenue is obtained from sales of books and online subscriptions. No financial assistance was obtained for this publication.
This article is eligible for Mainpro+ certified Self-Learning credits. To earn credits, go to https://www.cfp.ca and click on the Mainpro+ link.
La traduction en français de cet article se trouve à https://www.cfp.ca dans la table des matières du numéro de février 2023 à la page e38.
- Copyright © 2023 the College of Family Physicians of Canada
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