Timing of Medication

Introduction

I have encountered some patients who asked about the appropriate timing for taking their oral medication (morning, afternoon or night) when they were advised to take it once a day.

Generally, I inform them that the specific timing for taking the medicine is not crucial and they can select a suitable time that suits them best.

More importantly, they should take the medications at the same time each day to establish a regular habit.

Below are some medications that require specific timing.

NOTE: Administration of medication before, with or after food is discussed at a separate post.

Chronotherapy

Chronotherapy involves the administration of medication in coordination with the body's circadian rhythms to maximise therapeutic effectiveness and minimise/avoid adverse effects.

This is a promising aspect, but more extensive research is needed.

Time of Day When Physiological or Biochemical Functions Are At Peak

Time of Day When Symptoms are Most Frequent

Medications that Cause Drowsiness

Logically, medications that can cause drowsiness, such as benzodiazepines, opioids, first-generation antihistamines (e.g. chlorpheniramine, dexchlorpheniramine, promethazine) and muscle relaxants, are recommended to take closer to bedtime if possible. If patients are affected, do not drive or operate machinery.

ADHD Medications

Stimulants (e.g. methylphenidate) and atomoxetine are often given in the morning to control symptoms.

Antidepressants

Dosing instructions for antidepressants vary depending on the specific drug. Selective serotonin reuptake inhibitors, serotonin and norepinephrine reuptake inhibitors, tricyclic antidepressants, and monoamine oxidase inhibitors can cause either activating or sedating adverse reactions. Administer activating drugs in the morning and sedating drugs in the evening to avoid insomnia or daytime drowsiness, respectively. Some adverse reactions can be used as an advantage. For example, amitriptyline has sedative effects and may help patients sleep.

Morning: Escitalopram, fluoxetine, moclobemide, sertraline,
Bedtime: Agomelatine, fluvoxamine, mirtazapine, paroxetine, TCAs

Antihypertensive Drugs

As an overview, blood pressure follows a circadian rhythm, with BP levels falling during sleep and increasing in the early morning hours in most individuals. In patients with hypertension, a lack of fall in night-time BP (i.e. nondipping) and/or marked rise or surge in BP during the early morning hours is associated with a higher incidence of stroke and an increased risk for other cardiovascular complications, especially among the elderly.

In some studies, shifting at least one antihypertensive medication from the morning to the evening both restored the normal nocturnal blood pressure dip and reduced 24-hour mean blood pressure.

However, several blinded and unblinded trials found no difference in 24-h mean or nocturnal blood pressure with evening versus morning dosing of antihypertensive therapy and no effect on the proportion of dipping.

As shown above, the evidence on antihypertensive best administration time is actually in a mix. My personal stance is to take the antihypertensive medications consistently at a time (morning or night), do not keep on changing. If patient experienced dizziness post multiple antihypertensive medications, it might be a good idea to separate the administration time.

Aspirin for Preeclampsia

Bedtime administration of low dose aspirin (75 mg-150 mg) starting at 12-16 weeks gestation appears to be associated with greater protection from preeclampsia compared with administration in the morning.

Bisphosphonates

Because food may prevent absorption, oral bisphosphonates (e.g. alendronate, risedronate) should be taken in the morning, 30 to 60 minutes before breakfast.

Following administration, they should remain upright until after breakfast to avoid oesophageal or gastric irritation.

Diuretics

By altering the body's electrolyte composition, especially sodium, diuretics influence the amount of urine production. Teach patients to take these medication (e.g. hydrochlorothiazide, indapamide, spironolactone, bumetanide, frusemide) in the morning or early afternoon to avoid nocturia and subsequent sleep interruptions.

H₂ Receptor Antagonists

Bedtime dosing can help reduce overnight symptoms such as heartburn. Night-time acid secretion is primarily mediated by histamine.

Isosorbide Dinitrate

Nitrate tolerance has been a major problem with the use of nitrates as chronic antianginal therapy. As suggested in Lexicomp, the administration of isosorbide dinitrate should not be around the clock, but to allow nitrate-free interval of at least 14 hours for immediate release products and at least 18 hours for sustained release products.

Immediate release products: For twice daily dosing, consider administering at 8 am and 1 pm. For 3 times daily dosing, consider 8 am, 1 pm and 6 pm.
Sustained release products: Consider once daily in morning or twice-daily dosing at 8 am and between 1 pm and 2 pm.

Levothyroxine

To improve drug absorption, administer consistently in the morning on an empty stomach, at least 30 to 60 minutes before food. Alternatively, may consistently administer at night 3 to 4 hours after the last meal. Do not administer within 4 hours of calcium- or iron-containing products.

Oral Contraceptive Pills

It is very important to take oral contraceptive pills at the same time each day. If there is a missed dose, the contraceptive efficacy may be affected.

Prostaglandin Analogues for Glaucoma at Night

In open-angle glaucoma management, prostaglandin analogues (e.g. bimatoprost, latanoprost, tafluprost and travaprost) are typically first-line therapy. Because the medications take about 2 weeks to achieve their maximum therapeutic effect, follow-up for efficacy should occur no sooner than 2 weeks.

They are typically dosed only ONCE a day, preferably at evening for optimal effect:

Statins

At outpatient pharmacy, we often counsel patients to take statins at night. However, this statement is not universally applicable to all statins available in the market. It is rather a simplified way of remembering the dosing time and subsequently, improves patient compliance.

The shorter-acting statins, pravastatin and simvastatin, may slightly more effective if taken at bedtime compared to morning due to increased cholesterol production overnight when there is less food in the stomach.
However, rosuvastatin and atorvastatin, can be taken at any time of the day due to their long time of action.

Warfarin

Take warfarin tablets at approximately the same time each day. Most people take their daily warfarin dose in the evening. This allows the dose to be changed if necessary on the day that an INR result is obtained, rather than waiting until the next day.

Others

Morning

Canagliflozin - Take preferably before the 1st meal of the day.
Doxazosin Extended-Release Tablet - with morning meals
Ertugliflozin
Gliclazide MR Tablet - with breakfast
Moxonidine
Neratinib
Tacrolimus Prolonged Release Capsule - on empty stomach
Vastarel 80 mg XR Capsule - during breakfast
Vildagliptin - when used once daily dosing

Evening

Adapalene 0.1% and Benzoyl Peroxide 2.5% Gel (Epiduo)
Clindamycin 1% and Benzoyl Peroxide 5% Gel (Duac)
Lixisenatide
Lurasidone
Metformin XR - with evening meals
Montelukast
Rivaroxaban - with evening meals for nonvalvular atrial fibrillation

Bedtime

Adapalene 0.1% cream or gel
Ciclosporin 0.1% ophthalmic emulsion (Ikervis)
Donepezil
Efavirenz - on empty stomach
Fluocinolone Acetonide 0.01%, Hydroquinone 4% and Tretinoin 0.05% Cream (Tri-Luma) - at least 30 min before bedtime
Fosfomycin
Imiquimod 5% cream
Lemborexant
Perampanel
Senna
Strontium ranelate
Thalidomide - take at least 1 hour after food and preferably at night to avoid feeling sleepy during the day

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