From International Journal of Clinical Practice 
 
Optimal Time to Take Once-Daily Oral Medications in Clinical Practice CME
Posted 12/4/2008
 
Ling-Ling Zhu, MD; Quan Zhou, MD; Xiao-Feng Yan, MD; Su Zeng, MD 
Disclosures


Abstract and Introduction
Abstract

Currently only a few package inserts of once-daily medications specially define the dosing time, although sporadic studies have demonstrated administration time-dependent effects on the therapeutic outcome. Some chronotherapeutic approaches aim to diminish the occurrence of adverse drug reactions (ADRs) and hence better tolerance and medication compliance whereas most of the chronotherapies are recommended to improve therapeutic efficacy. The administration time-dependent efficacy seems not a common feature of drugs within the similar therapeutic or structural class and it is related to kinds of drugs, pathophysiologic status, clinical symptoms and feedback from patients. Doctors, pharmacists and nurses should know what kind of drug has requirement for optimal dosing time, and realize that better efficacy and lower incidence of ADRs may be achieved by rational arrangement of administration schedule. In order to promote medication compliance, it is essential to provide patient education regarding differences between conventional and chronotherapeutic approaches and pathophysiologic benefits of chronotherapy.
Introduction

More and more once-daily oral medications are emerging. As members of medication therapy management (MTM) in clinical practice, doctors, pharmacists and nurses always face a common problem, i.e. what is the optimal time for the patients to take these drugs. Is it in the morning, in the early evening, at bedtime or at any time? Pitifully, only a few package inserts specially define the dosing time. This critical problem introduces a concept of chronotherapy, which is the optimisation of drug effects and/or minimisation of adverse drug reactions (ADRs) by timing medications with regard to biological rhythms.[1] Numerous sporadic clinical trials have demonstrated administration time-dependent effects of once-daily medications on therapeutic outcome. So, the members of MTM have a lot to relearn about how to use both old and new once-daily drugs effectively. However, a systematic review update of chronotherapy of once-daily medications in clinical practice is not yet available.

Meanwhile, a patient who is being switched from a conventional regimen to a chronotherapeutic regimen may not fully understand the fundamentals behind the change. This in turn may result in poor medication compliance, or, even worse, that the patient may discontinue taking the medicine. So it is essential for the members of MTM to remind themselves to promote medication compliance by providing education to the patient regarding the differences between conventional and chronotherapeutic approaches, and pathophysiologic benefits of chronotherapy. This paper focuses on this respect and aims to describe that better efficacy and lower incidence of ADRs may be achieved by arranging optimal dosing time of once-daily medications.

Antigastric-secretion Drugs

Proton pump inhibitor (PPI) and H2 receptor antagonists (H2RAs) are two major acid-suppressing drugs used for symptom relief, healing of erosive oesophagitis, resolution of peptic ulceration, reducing risk for non-steroidal anti-inflammatory drug (NSAID)-induced mucosal damage and prevention of disease recurrence.

It was found that the optimal time of morning vs. evening administration of PPIs depended on the kind of PPI, clinical symptoms and feedback from the patients. Morning dosing of pantoprazole was significantly superior to evening dosing with regard to 24-h intragastric pH and it should be recommended for the treatment of acid-related diseases.[2] This administration schedule is also specially defined in prescribing information for PANTOLOC® (pantoprazole tablets; ALTANA Pharma, Konstanz, Germany). However, dosing time is not yet defined in the package inserts of LOSEC MUPS® (omeprazole magnesium tablets; AstraZeneca AB, Södertälje, Sweden), Pariet® (rabeprazole tablets; Esai Co Ltd, Tokyo, Japan), Prevacid® (lansoprazole capsules; TAP Pharmaceutical Products, Lake Forest, IL, USA) and Nexium® (esomeprazole magnesium tablets; AstraZeneca Pharmaceutical Co Ltd, Wilminton, DE, USA). Morning dosing of omeprazole is preferable for patients with reflux induced by physical activity whereas evening dosing is clearly preferable for patients with nocturnal reflux.[3] Lansoprazole is routinely administered in the morning, but patients with mainly nocturnal symptoms may be best treated by evening dosing.[4] Evening dosing of rabeprazole (20 mg) normalises more effectively the total oesophageal exposure and provides significantly better control of nocturnal gastro-oesophageal reflux disease than morning dosing.[5] One potential reason for the better efficacy of the evening dosing of PPI could be the higher caloric intake at dinner compared with breakfast and the theory that the more potent the stimulus, the more proton pumps that will be exposed for consecutive inhibition by the PPI.

As for once daily H2RAs such as ranitidine, famotidine and roxatidine, early evening dosing (18:00 h) provides better control of nocturnal acidity and more satisfactory control of 24-h acidity than dosing at bedtime (22:00 h) and hence is suggested for optimisation of therapeutic efficacy.[6-9] A possible explanation for the improved efficacy is that high plasma concentrations of oral H2RAs are present when stimuli to acid secretion are high after dinner.
Drugs Acting on Cardiovascular System

In the cardiovascular patient, the focus of chronotherapy would be to optimally improve the prevention and treatment of diseases according to circadian variations and the kinetic and dynamic properties of drugs. Table 1 lists the optimal dosing time of common drugs acting on cardiovascular system.

Calcium Channel Blockers

Several studies compared the efficacies of morning vs. evening administration of calcium channel blockers (CCBs) in patients with essential hypertension. Administration time-dependent effect on blood pressure (BP) seems not a common feature of CCBs. It is related to the kinds of CCBs.
Isradipine Sustained Release

Once daily dosing time is not yet defined in the current package insert of DynaCirc CR® (isradipine controlled release tablets; Reliant Pharmaceuticals, Inc., Liberty Corner, NJ, USA). A randomised, double-blind, placebo-controlled study revealed that the BP-lowering effect of isradipine sustained release in 18 patients with uncomplicated essential hypertension (mean age 55 ± 6 years) was regardless of dosing time.[10] However, an evening regimen seems more apt than a morning regimen to obtain the therapeutic goal in hypertensive patients with chronic renal failure. Only the evening administration reset the normal synchronisation of the 24-h BP and heart rate (HR) profiles. The non-dipper BP profile could be normalised with evening but not morning dosing.[11] The difference in the results of these two studies implies that the comorbidity factor (i.e. chronic renal failure) exerts different administration time-dependent effect of isradipine sustained release on BP in hypertensive patients. It may be explained by the systolic and diastolic BP fall in the night, which attenuated in chronic renal failure patients, in contrast to the essential hypertension in which the nocturnal BP fall was preserved.
Nifedipine GITS

In previously untreated essential hypertension patients with grade 1–2, the efficacy of 60 mg/day nifedipine gastrointestinal therapeutic system (GITS) in non-responders to the initial 30 mg/day dose was twice as great with bedtime when compared with morning dosing. Bedtime administration significantly reduces the incidence of oedema as an ADR by 91% and the total number of all ADRs by 74% when compared with morning dosing. Interestingly, dosing time effect on the efficacy was closely related to the dosage of nifedipine GITS. The dosing time of 30 mg/day nifedipine GITS has no impact on the therapeutic efficacy.[12,13] Although once daily dosing time is not yet defined in prescribing information for Adalat XL® (nifedipine GITS), the dose-dependent enhanced efficacy and the markedly improved safety profile of bedtime as compared with morning dosing should be taken into account when prescribing nifedipine GITS in the treatment of essential hypertension.
Amlodipine

An open, randomised cross-over study in 12 patients with mild-to-moderate essential hypertension for 3 weeks showed that morning dosing of amlodipine lowered daytime BP slightly more than evening dosing, but this did not achieve statistical significance.[14] However, a perspective, double-blind, randomised, crossover study, in 62 Chinese patients with mild-to-moderate essential hypertension for 6 weeks, revealed that 24-h diastolic BP load and nighttime BP load were significantly greater with evening dosing compared with morning dosing. Nocturnal fall of BP was greater with morning dosing than with evening dosing.[15] Thus, although once daily dosing time is not yet specially defined in the current package insert of Norvasc® (amlodipine tablets; Pfizer, New York, NY, USA), the optimal dosing time of amlodipine may be morning.
Nisoldipine Extended Release

A randomised, crossover study in 85 patients with mild-to-moderate hypertension revealed that the timing of nisoldipine extended release administration had no effect on the mean changes in BP and HR over a 24-h period. However, a significantly greater effect on awake diastolic BP following 4-week 20 mg once-daily therapy was observed with morning dosing compared with evening dosing. In addition, small increases in sleep and early morning HR were seen with evening compared with morning administration of nisoldipine.[16] So, morning dosing may be preferred for nisoldipine extended release.
Cilnidipine

An open randomised crossover study in 13 essential hypertension patients concluded that cilnidipine efficacy was regardless of administration time.[17] However, bedtime but not morning dosing significantly reduces nocturnal BP and is useful for patients with uncontrollable morning hypertension.[18] Large-sample, double-blind randomised crossover study is essential for the evaluation of the dosing-time dependent efficacy of cilnidipine.
Verapamil Extended-release (Covera-HS®)

Covera-HS (Pfizer) uses the controlled-onset, extended release delivery system. The tablet consists of multiple coats. The outermost coat is composed of a semi-permeable membrane that regulates the amount of water that can penetrate into the tablet. Water from the GI tract will continue to saturate this layer at a fixed rate until the second coat is reached. The second coat will continue to absorb water but temporarily impedes any fluid from reaching the inner core of active drug. After 4–5 h, fluid eventually penetrates into the third coat, which osmotically expands, pushing verapamil out of the tablet at a constant, fixed rate. According to this design principle, Covera-HS should be given at bedtime so that the bedtime dosing can achieve a maximum plasma concentration of verapamil in the early morning and the extended release over the 24-h time period.[19]
Diltiazem Extended Release (Cardizem LA®)

Compared with morning administration, bedtime dosing of Cardizem LA® (Biovail, Mississauga, ON, Canada) provides enhanced 24-h control, optimal morning protection and an additional 3.3 mmHg diastolic BP reduction in the critical morning hours, when angina or hypertensive patients are at the greatest risk.[20] A possible explanation for the improved efficacy is that bedtime administration exhibited 22% greater bioavailability compared with morning administration under steady-state conditions and also provided more than twofold higher plasma diltiazem levels in the critical morning hours.[21]
Angiotensin II Receptor Blockers

Although once daily dosing time is not yet specially defined in the current package inserts of Aprovel® (irbesartan tablets; Sanofi Winthrop Industrie, Ambares, France), Diovan® (valsartan capsules; Novartis, East Hanover, NJ, USA), Micardis® (telmisartan tablets; Boehringer Ingelheim, Ridgefield, NJ, USA), Blopress® (candesartan cilexetil tablets; Takeda Pharmaceutical, Osaka, Japan) and Benicar® (olmesartan medoxomil tablets; Sankyo, Tokyo, Japan), the efficacies of morning vs. evening administration of angiotensin II receptor blockers (ARBs) in essential hypertension patients were compared in several studies. Inconsistent findings were identified. The administration time-dependent efficacy seems not a common feature of ARBs. It is related to the kinds of ARBs and the dipper status of patients.

Administration time-dependent effects of losartan have not been documented. There was no significant difference in antihypertensive efficacy between administration schedules (morning vs. evening) following a 6-week therapy with 100 mg irbesartan in 20 patients with uncomplicated, mild-to-moderate essential hypertension.[22] Dosing time did not exert statistically significant differences on the efficacy of olmesartan medoxomil (20–40 mg) after 12 weeks of morning vs. evening dosing in 18 diurnally active subjects with uncomplicated, mild to moderate, essential hypertension.[23]

The optimal time of valsartan is bedtime. Bedtime administration as opposed to administration during wakening improves the sleep time-relative BP decline towards a more dipper pattern without loss in 24-h efficacy. It also results in a significant increase in the percentage of controlled patients after treatment, and a significant reduction in urinary albumin excretion. Time of treatment can be chosen according to the dipper status of a patient.[24,25]

A study in 42 young men with mild or moderate essential hypertension concluded that telmisartan (40 or 80 mg) should be given in the morning, in that a statistically significant reduction of morning diastolic BP was only found in patients treated with telmisartan in the morning, as opposed to bedtime dosing, although the systolic BP values in all the time intervals were comparable.[26] More recently, bedtime dosing of telmisartan was recommended. As opposed to morning dosing, bedtime dosing improved the sleep time-relative BP decline towards a more dipper pattern without loss in 24-h efficacy, and achieve significantly better nocturnal BP regulation following a 12-week therapy with 80 mg telmisartan in 215 patients, mean age 46.4 ± 12.0, with essential hypertension.[27] The findings indicate that the dosing time of telmisartan can be chosen according to the dipper status of a patient. Further studies are needed to address whether age status may influence administration time-dependent effects of telmisartan on BP control in hypertensive patients.

As for candesartan cilexetil, the optimal dosing time is during awakening. The efficacy of candesartan cilexetil (8 mg once daily) was evaluated after 3-month antihypertensive therapy in 60 patients, mean age 60 ± 6 years, with mild-to-moderate essential hypertension. Administration upon awakening, as opposed to at bedtime, seems to provide a superior control of mean 24 h and mean daytime BP.[28]


Angiotensin-converting Enzyme Inhibitors

Although once daily dosing time is not yet defined in the current package inserts of Lotensin® (benazepril hydrochloride tablets), Accupril® (quinapril hydrochloride tablets), Tritace® (ramipril tablets) and MAVIK® (trandolapril tablets), the efficacies of morning vs. evening administration of angiotensin-converting enzyme inhibitors (ACEIs) in essential hypertension patients were compared in several studies.

A single-blind crossover study in 10 hypertensive patients receiving a single dose of 10 mg benazepril concluded that morning administration more effectively covered the whole 24 h than an evening dose.[29] It is worthy to study whether chronological effect still exists during maintenance therapy with benazepril. As for perindopril (4 mg), the effect of reducing the early morning peak BP rise tended to be greater with the 21:00 h dose. However, the 09:00 h dose had an effect that persisted for > 24 h but the effect of the 21:00 h dose had dissipated 18 h after the dose.[30] It indicates that the response profile obtained with perindopril cannot be transformed from one dose time to another automatically and that chronobiology has important effects on the drug's action. Currently, morning dosing is recommended in prescribing information for Acertil® (Servier, Orléans, France). In clinical practice, the 21:00 h dose should be titrated to the next dose range.

Evening administration of quinapril (20 mg) seems preferable, because it produces a more sustained and stable 24-h BP control compared with the morning dosing, probably through a more favourable modulation of tissue angiotensin-converting enzyme inhibition or effect on the adrenergic-induced rise in BP that occurs during early morning hours. A partial loss of effectiveness was observed during night if quinapril was given in the morning.[31]

The optimal dosing time of ramipril is evening or bedtime. Evening intake of 5 mg ramipril had a significantly more favourable effect on haemodynamics than morning dosing in 30 patients with essential hypertension stage II.[32] Beneficial effects on cardiovascular morbidity and mortality seen with ramipril in the Heart Outcomes Prevention Evaluation study were related to its improved effect (i.e. increase in the diurnal/nocturnal BP ratio) on the non-dipping BP pattern of the participating cohort of patients receiving ramipril at bedtime.[33]

The optimal dosing time of trandolapril is bedtime. In the bedtime-administered group, prewaking and morning systolic BP were significantly decreased by 11 mmHg and by 8.4 mmHg respectively. On the other hand, in the morning-administered group, the reduction of prewaking and morning systolic BP did not reach the level of statistical significance. Bedtime administration results in a safe and effective means of controlling morning BP without the induction of excessive BP reduction nocturnally.[34]

Blood pressure changes as a result of once daily administration 20 mg lisinopril at three different times (8:00, 16:00 and 22:00 h) were assessed in 40 patients with primary mild-to-moderate hypertension. The chronobiological analysis showed a greater reduction of systolic and diastolic morning BP after dosing at 22:00 h, although BP circadian rhythm was unmodified. A possible explanation for the improved efficacy of administration at 22:00 h that peak serum concentrations of lisinopril occur within about 7 h when cardiovascular events are most frequent.[35]

Dry cough as an ADR is observed in 12% or more patients treated with enalapril. This ADR might be diminished or eliminated by a switch to nighttime administration in patients who complain of cough during treatment with enalapril in the morning.[36,37] Plasma bradykinin, which is likely to be involved in the mechanism of enalapril-induced cough, was found to be affected by the dosing time. It tended to increase following enalapril administration at 10:00 h, but not at 22:00 h. In addition, BP was still significantly reduced 24 h after administration of enalapril at 22:00 h, but not at 10:00 h, indicating the prolonged antihypertensive action of enalapril after administration at 22:00 h. Thus, nighttime dosing is preferred for enalapril.
Beta-blockers

Beta-blockers are still recommended as first-line therapy in many hypertensive patients, particularly those at high risk for cardiovascular disease. They are also indicated for other cardiovascular disorders such as congestive heart failure and postmyocardial infarction.

Clinical usefulness of chronotherapy with carvedilol was observed by Koga et al.[38] Carvedilol, as a single dose in the morning or evening in a randomised crossover open-label protocol, was added to therapy regimen in nine patients who had been treated with first-line antihypertensive drugs for 4 weeks but still had high BP in the morning. Evening carvedilol administration after 4 weeks significantly suppressed the morning surge while morning administration lacked a significant anti-surge effect. The addition of chronotherapy with carvedilol may be an effective way to suppress morning surges of hypertension. Carvedilol phosphate extended-release capsule (COREG CR; GlaxoSmithKline, Research Triangle Park, NC, USA) utilises proprietary micropump technology that controls the delivery of carvedilol and helps to maintain appropriate concentrations in the body over a 24-h span with once-daily dosing. It should be taken once daily in the morning with food, as described in its current package insert. A phase I clinical trial (study ID: SK&F-105517/906) sponsored by GlaxoSmithKline may provide evidence for favouring morning dosing of COREG CR.[39] In that clinical trial, evening administration of carvedilol CR (80 mg) resulted in an approximate 10% decrease in the area under the curve of both R(+)- and S(–)-carvedilol, a 15–19% decrease in Cmax of both R(+)- and S(–)-carvedilol and a decrease in the rate of absorption of both R(+)- and S(–)-carvedilol (tmax delayed approximately 1.5 h) compared with morning administration. As for metoprolol succinate sustained-release (Betaloc ZOK; AstraZeneca Pharmaceutical Co Ltd), it is recommended for once daily treatment and is preferably taken together with the morning meal according to its prescribing information. Moreover, morning hypotension and daytime fatigue can be avoided when metoprolol succinate is prescribed with the breakfast.[40] A chronotherapeutic formulation of propranolol extended release (Innopran XL™; Reliant Pharmaceuticals, Inc.) was approved for the treatment of hypertension because of its appropriate pharmacokinetics. Multiple-dose study of this medication showed that bedtime dosing was preferable in that it resulted in trough drug blood concentration during the night because of the intentional delay of propranolol release for 4–5 h, peak drug concentration between 4 and 10 AM, and an elevated plateau of drug concentration in the afternoon and early evening.[41]
Antihyperlipidaemic Drugs

3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors, also known as statins, are effective in primary and secondary prevention of cardiovascular events in patients with hyperlipidaemia. The rate of cholesterol biosynthesis is at its highest after midnight and lowest during the morning and early afternoon. The circadian rhythm is caused by diurnal changes in the activity of hydroxymethylglutaryl coenzyme A reductase. In general, statins with a shorter half-life (i.e. lovastatin, simvastatin and fluvastatin) are more effective in lowering low-density lipoprotein-cholesterol (LDL-C) when taken in the evening, whereas statins with longer half-lives (i.e. fluvastatin extended release, rosuvastatin and atorvastatin) have similar lipid-lowering effects when taken during any time of the day.[42-46]

The systemic bioavailability of pravastatin administered at bedtime was 60% decreased compared with that following a morning dose. However, the efficacy of pravastatin administered in the evening was marginally more effective than that after a morning dose. Chronophysiologic effect outweighing chronopharmacokinetic effect may be the underlying mechanism. In the current package insert of Mevalotin® (Sankyo), it is also recommended to be taken once daily at bedtime. New evidence has shown significant administration time-dependent influence on lipid and non-lipid related effects of atorvastatin in 152 patients undergoing PCI. One year clinical follow-up data in these patients showed evening intake of atorvastatin (40 mg/day for the first month and 10 mg/day thereafter) was associated with less frequent occurrence of major cardiac events, a low restenosis rate, a trend towards low pre- and postprocedural high-sensitivity C-reactive protein levels, a more pronounced decrease in total cholesterol, LDL-C and triglyceride values, an increase in high-density lipoprotein-cholesterol (HDL-C) levels and better improvement of endothelial dysfunction compared with morning dosing.[47]

As for ezetimibe, morning intake was equally effective for total and LDL-C, but there was a benefit with morning intake considering the increase in HDL-C.[48] However, dosing time is not yet defined in the prescribing information for Zetia® (ezetimibe tablets; Schering-Plough, Kenilworth, NJ, USA). Vytorin® (ezetimibe/simvastatin tablet; Merck/Schering-Plough, Kenilworth, NJ, USA) is more effective when taken in the evening according to its prescribing information. As to bezafibrate extended release, total cholesterol-lowering efficacy was regardless of dosing time but HDL-C increased more with morning dosing.[49] Fenofibrate extended release morning intake was equally effective as evening intake.[50]
Doxazosin GITS

Doxazosin GITS (Cardura® XL; Pfizer) is usually taken once a day in the morning with breakfast according to its prescribing information. However, a randomised study in 91 patients with grade 1–2 essential hypertension (mean age 56.7 ± 11.2 years) demonstrated that doxazosin GITS (4 mg) therapy upon awakening for 3 months failed to provide full 24-h therapeutic coverage whereas bedtime dosing significantly reduced BP throughout the 24 h.[51] Interestingly, dosing time did not appear to influence the efficacy and safety of doxazosin in patients with benign prostatic hyperplasia (BPH) after 24 weeks of treatment, suggesting that there is no need to restrict the administration of doxazosin to the evening in BPH patients.[52]
Aspirin

Low-dose aspirin is commonly prescribed for the primary and secondary prevention of cardiovascular and cerebrovascular events. Dosing time is not yet defined in the current package insert of Bayaspirin®; Bayer, Leverkusen, Germany. However, recent evidence showed that 100 mg aspirin administered at bedtime, but not on awakening, has a beneficial effect on ambulatory BP. BP was slightly elevated after dosing on awakening whereas a significant BP reduction (decrease of 7.2/4.9 mmHg in systolic/diastolic BP) was observed in patients who was receiving aspirin before bedtime.[53] The reduction in nocturnal BP mean was double in non-dippers (11.0/7.1 mmHg) compared with dippers (5.5/3.3 mmHg; p < 0.001). The study corroborates significant administration time-dependent effect of low-dose aspirin on BP, mainly in non-dipper hypertensive patients.[54] Morning dosing of aspirin has its lowest protective value against cardiovascular events during the night and early morning. In contrast, highest plasma level of aspirin taken late evening (22:00 h) would be reached prior to the peak-incidence of thromboembolic disorders. Bedtime dosing would thus fit better in the circadian scheme of the occurrence of stroke, thus resulting in a significantly more effective prevention.[55]
Isosorbide Mononitrate Sustained-release Formulation

Elantan LA® (Schwarz Pharma, Monheim, Germany), a long-acting isosorbide mononitrate formulation, should be given upon awakening. About 30% of its dose is available for immediate release and the remaining 70% is gradually released over time. It has a quick onset of action and effects are evident for up to 17 h. Its pharmacokinetic profile accords with the circadian variation in cardiovascular disease and hence maximised protection against the morning surge in myocardial ischaemia. As for IMDUR® (AstraZeneca Pharmaceutical Co Ltd), once-daily administration in the morning, after awakening, is recommended in its package insert so that it produces a plasma nitrate profile that is high enough to give anti-anginal protection during the daytime, but low enough during the latter part of the dosage interval to avoid the development of tolerance.

Diuretics are currently recommended as first-line therapy for the treatment of hypertension. In addition, they remain an important component in the treatment of heart failure. Indapamide and hydrochlorothiazide should be given in the morning. The urinary Na/K ratio in the patients is increased significantly and thus fewer side effects by a switch to morning-time administration. Efficacy of torasemide (5 mg/day) in 58 patients with grade 1–2 essential hypertension was significantly higher with bedtime dosing as compared with the administration of the drug on awakening. The percentage of patients with controlled ambulatory BP after 6 weeks treatment was also higher after bedtime treatment (54% vs. 27%). In addition, a full 24-h therapeutic coverage was observed only when torasemide was given before bedtime.[56] With regard to the safety profile, two patients presented secondary effects (abdominal pain, diarrhoea) in morning dose, and four patients taking the drug at bedtime reported nicturia. The differences in efficacy and therapeutic duration should be taken into account when prescribing torasemide for the treatment of essential hypertension. To reduce nighttime urination, take the once-daily hydrochlorothiazide based fixed-dose combination before 6 PM and preferably in the morning. These medications include beta-blocker/hydrochlorothiazide, ARB-hydrochlorothiazide and ACEI-hydrochlorothiazide.

Antidepressants

Chronotherapies with antidepressants may bring additional therapeutic advantages. Clomipramine (150 mg) once daily was given to 30 patients with depression at three different times of the day (morning, noon, or before bedtime), using a double-blind method over a 4-week period. Beneficial effects were closely related to the administration time, with the most effective result being observed with the noon administration.[57]

On the contrary, dosing time has no influence on the efficacies of citalopram, sertraline and venlafaxine sustained release formulations, as indicated in standard drug information. Fluoxetine is recommended to be administered in the morning according to the package insert of Prozac® (fluoxetine capsules; Eli Lilly & Co, Indianapolis, IN, USA), although Usher et al.[58] revealed that the efficacy and toleration were regardless of the dosing time. Fluvoxamine is better tolerated with bedtime dosing. Mirtazapine is a potent blocker of the histamine receptors and it tends to have a somewhat sedative effect, thus favouring administration at bedtime. Fluvoxamine maleate and mirtazapine are also recommended to be given at bedtime according to their prescribing information. Paroxetine is usually administered in the morning. Morning dosing can decrease the occurrence of insomnia as an ADR, whereas bedtime dosing is preferable if patients feel drowsy after morning dosing. The olanzapine/fluoxetine combination has demonstrated effectiveness in the treatment-resistant depression. Administration once daily in the evening is specially defined in the package insert of SYMBYAX® (olanzapine and fluoxetine capsules; Eli Lilly & Co).
Drugs Acting on Metabolism and Endocrine System
Levothyroxine Sodium

Levothyroxine sodium is a good therapeutic choice for hypothyroidism. Standard drug information resources recommend that levothyroxine sodium be taken half an hour before breakfast. However, a pilot-study in 12 patients with primary hypothyroidism demonstrated that taking the same dose of levothyroxine at bedtime, when compared with that during morning, might be better. Bedtime dosing was associated with higher thyroid hormone concentrations and lower thyroid stimulating hormone concentrations compared with morning dosing. A large double-blinded randomised study will need to be performed to confirm these results. A better GI uptake of levothyroxine sodium during night may be the underlying mechanism for the findings of this study.[59] Taking medication at bedtime instead of in the morning could have major implications for many thyroid patients.
Hypoglycaemic Drugs

Patients with diabetes mellitus should be offered individualised therapy. Hypoglycaemic effects of glimepiride, pioglitazone and rosiglitazone are regardless of the administration time.[60] However, Glucotrol XL (glipizide controlled-release tablet; Pfizer), Avandaryl® (rosiglitazone maleate and glimepiride tablets; GlaxoSmithKline) and Diamicron MR® (gliclazide modified release tablets; Les Laboratoires Servier, Gidy, France) should be given once daily with breakfast. Disturbances of the gut such as diarrhoea, constipation, indigestion and nausea can be avoided or minimised if gliclazide modified release tablet is taken with the breakfast.
Anti-asthma Drugs

Appropriate anti-asthma therapy can alleviate symptoms and reduce morbidity. Optimal dosing time is required for some anti-asthma drugs. Bambuterol (terbutaline prodrug) and montelukast are recommended to be taken at bedtime, as defined in the current package inserts of Bambec (bambuterol tablet; AstraZeneca Pharmaceutical Co Ltd) and Singulair® (montelukast sodium tablets; Merck & Co, Cramlington, UK). Evening administration of bambuterol in comparison with morning administration produced enhanced bronchodilator effect at 7 AM, which seemingly was because of the elevated terbutaline level maintained during the morning hours following evening administration. The mean 7 AM plasma terbutaline concentration was 15.6 nmol/l with evening bambuterol, while it was only 10.5 nmol/l with morning administration.[61] Evening dosing seems to be preferable for pranlukast and once-daily theophylline preparation so that it can achieve higher therapeutical levels at night and in the morning when asthmatics are at the greatest risk of developing bronchospasm.[62,63]
Non-steroidal Anti-inflammatory Drugs

Non-steroidal anti-inflammatory drugs are necessary in common ailments such as osteoarthritis and degenerative joint disease. Potential therapeutic benefit of NSAIDs might be gained by arranging optimal dosing time. Evening dosing of indomethacin sustained release was most effective in osteoarthritis patients with predominant nocturnal or morning pain whereas morning or noon ingestion was the most effective in patients with maximum afternoon or evening pain. The analgesic effect was increased by about 60% when the NSAID was taken at the preferred time (about 6 h prior to the usual time of day of worse osteoarthritic pain) compared with when it was ingested at the non-preferred times of the day.[64,65] With regard to the safety profile, a double-blind, cross-over trial of a 3-week duration involving 66 patients concluded that adverse effects were consistently greater in occurrence and in severity when indomethacin sustained release was ingested at 8 AM than at any other time of the day.[66] Morning dosing of ketoprofen controlled release (200 mg) increased the efficacy without reducing the tolerability in patients with osteoarthrosis when compared with evening dosing. The reduction in the degree of pain in the afternoon and in the evening was significantly higher for the morning dose.[66] However, total and GI side effects were twofold greater in patients taking ketoprofen in the morning than at night, as described in a double-blind trial with 118 osteoarthritis outpatients receiving a 200 mg ketoprofen slow-release tablet.[67] Bruguerollea concluded that evening dosing of NSAIDs would be better tolerated by diurnally active persons compared with the morning dosing and patients with high risk of GI irritation should be advised to avoid taking NSAID early in the morning.[68] As for celecoxib (a cyclooxygenase-2 specific inhibitor), the efficacy of regimen (200 mg once daily) in the management of osteoarthritis of the knee or hip is regardless of the dosing time.[69]
Discussion

It is particularly noteworthy that a difference between administration schedules (morning vs. evening) has been found where it is not expected, i.e. with amlodipine, a drug with a long half-life of 35–45 h. Thus, it indicates that all long-lasting agents should be properly studied to evaluate the safety and efficacy when they are administrated in the morning or in the evening.

Chronopharmacokinetics refers to time-dependent changes in kinetics, which may proceed from circadian variations at each step, e.g. absorption, distribution, metabolism and excretion. Interestingly, the optimal dosing time sometimes is not the time expected from the perspective of chronopharmacokinetics. Aspirin is a representative example. Its bioavailability in the morning is twice as high as in the afternoon.[70] Taking into account this chronopharmacokinetic characteristic, researches in early years recommended morning dosing of aspirin. However, recent evidence-based data favour bedtime dosing of low-dose aspirin.[53-55]

The administration time-dependent efficacy seems not a common feature for drugs within the similar therapeutic or structural class. It is related to kinds of drugs, pathophysiologic status, clinical symptoms and feedback from patients. Typical cases were observed with PPIs, CCBs, ARBs, ACEIs and beta-blockers. Further studies are needed to determine whether administration time-dependent effects will be observed with drugs of which morning and evening dosing have not been compared. For example, whether administration time-dependent effects of losartan exist has not been documented, although the relevant studies have been conducted for the other ARBs (i.e. irbesartan, valsartan, telmisartan, olmesartan medoxomil and candesartan cilexetil).

In clinical practice, members of MTM need to know the basis for chronotherapy of diseases. For example, the non-dipper circadian BP pattern represents a risk factor for left ventricular hypertrophy, microalbuminuria, cerebrovascular disease, congestive heart failure, vascular dementia and myocardial infarction. The normalisation of the circadian BP pattern to a dipper profile is a novel therapeutic goal.[71] Thus, if a drug administered at bedtime as opposed to morning dosing improved the sleep time-relative BP decline towards a more dipper pattern without loss in 24-h efficacy, optimum dosing time of this drug is at bedtime.

Therapeutic strategies in resistant diseases (e.g. resistant hypertension) include adding another drug or changing drugs for a better synergic combination. However, the situation might be improved if chronotherapeutic approach is introduced. For instance, Hermida et al.[72] evaluated the impact on the circadian pattern of BP by modifying the dosing time without increasing the number of prescribed drugs. Results indicate that, in patients with resistant hypertension, dosing time may be more important for BP control and for the proper modelling of the circadian BP pattern rather than just changing the drug combination.

Biological rhythm-dependent differences in the pharmacokinetics and pharmacodynamics of once-daily medications may be altered with other factors such as comorbidity conditions and aging. For example, chronic renal failure might result in different administration time-dependent effects of isradipine sustained release on BP in hypertensive patients.[10,11] Chronopharmacological variations may be related to ageing. For example, administration-time effects of telmisartan were detected only in mid-aged but not in young subjects.[26,27]

Sidebar: Review Criteria

Relevant literature was identified by performing Pubmed and Google Scholar searches until end of 2007. The MeSH terms used involve drug administration schedule, chronotherapy, chronopharmacology, circadian rhythm, morning and evening dosing and clinical trials. Other key words include chronopharmacokinetics, chronopharmacodynamics, morning vs. evening administration, morning and bedtime dosing and administration time-dependent effects. Available related package inserts and prescribing information were also referenced.

Message for the Clinic

Better efficacy and lower incidence of adverse drug reactions may be achieved by optimal timing of once-daily medicines. Doctors, pharmacists and nurses have a lot to relearn about how to use both old and new once-daily drugs effectively, and promote medication compliance by providing education to the patient regarding the differences between conventional and chronotherapeutic approaches, and pathophysiologic benefits of chronotherapy.
Acknowledgements

We also thank H. Grassos for data on administration time-dependent effects of candesartan. Dr H. Grassos is from Hypertension unit, Western Attica General Hospital, Athens, Greece.
Funding Information

Funding for the article is provided by Zhejiang Provincial Bureau of Education (No. 20070227), Zhejiang Medical Association (No. 2007ZYC18) and Association of Zhejiang Hospital Administration (No. 2007AZHA-KEB312).
Author Contributions

L.-L. Zhu and Q. Zhou put forward the viewpoint and designed this study; Q. Zhou, X.-F. Yan performed the literature review and data analysis/interpretation; L.-L. Zhu and Q. Zhou wrote the paper and S. Zeng was involved in the critical revision of the article.
Reprint Address

Quan Zhou, Pharmacist Clinical Specialist, Department of Clinical Pharmacy, The 2nd Affiliated Hospital, School of Medicine, Zhejiang University, Zhejiang 310009, China; Tel.: + 86 571 8778 3891; Fax: + 86 571 87213864; Email: zhouquan142602@zju.edu.cn

Conclusions

Members of MTM should know what kind of drug has requirement for optimal dosing time, and realize that better efficacy and lower incidence of ADRs may be achieved by rational arrangement of administration schedule. In order to promote medication compliance, it is essential to provide patient education regarding differences between conventional and chronotherapeutic approaches and pathophysiologic benefits of chronotherapy. For those once-daily medications without specific requirements for dosing time, they should be taken at the same time every day. It should also be borne in mind that medication compliance is a matter-of-course concern even if there is optimal time to take once-daily medications according to the chronotherapy principles.