doi: 10.1111/j.1742-1241.2008.01871.
1
Department of Geriatrics, The
2nd Affiliated Hospital, School
of Medicine, Zhejiang
University, Zhejiang, China
2
Department of Clinical
Pharmacy, The 2nd Affiliated
Hospital, School of Medicine,
Zhejiang University, Zhejiang,
China
3
Department of Pharmaceutical
Analysis & Drug Metabolism,
College of Pharmaceutical
Sciences, Zhejiang University,
Zhejiang, China
Correspondence to:
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
Disclosures
No conflicts of interest were
declared in relation to this
article.
1560
REVIEW ARTICLE
Optimal time to take once-daily oral medications
in clinical practice
L.-L. Zhu,1 Q. Zhou,2 X.-F. Yan,2 S. Zeng3
SUMMARY
Review Criteria
Currently only a few package inserts of once-daily medications specially define the
Relevant literature was identified by performing
dosing time, although sporadic studies have demonstrated administration time-
Pubmed and Google Scholar searches until end of
dependent effects on the therapeutic outcome. Some chronotherapeutic approaches 2007. The MeSH terms used involve drug
aim to diminish the occurrence of adverse drug reactions (ADRs) and hence better administration schedule, chronotherapy,
tolerance and medication compliance whereas most of the chronotherapies are rec- chronopharmacology, circadian rhythm, morning
ommended to improve therapeutic efficacy. The administration time-dependent effi- and evening dosing and clinical trials. Other key
cacy seems not a common feature of drugs within the similar therapeutic or words include chronopharmacokinetics,
structural class and it is related to kinds of drugs, pathophysiologic status, clinical chronopharmacodynamics, morning vs. evening
administration, morning and bedtime dosing and
symptoms and feedback from patients. Doctors, pharmacists and nurses should
administration time-dependent effects. Available
know what kind of drug has requirement for optimal dosing time, and realize that
related package inserts and prescribing information
better efficacy and lower incidence of ADRs may be achieved by rational arrange- were also referenced.
ment of administration schedule. In order to promote medication compliance, it is
essential to provide patient education regarding differences between conventional Message for the Clinic
and chronotherapeutic approaches and pathophysiologic benefits of chronotherapy. 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.
tively. However, a systematic review update of chro-
Introduction
notherapy of once-daily medications in clinical
More and more once-daily oral medications are practice is not yet available.
emerging. As members of medication therapy man- Meanwhile, a patient who is being switched
agement (MTM) in clinical practice, doctors, phar- from a conventional regimen to a chronotherapeu-
macists and nurses always face a common problem, tic regimen may not fully understand the funda-
i.e. what is the optimal time for the patients to take mentals behind the change. This in turn may
these drugs. Is it in the morning, in the early even- result in poor medication compliance, or, even
ing, at bedtime or at any time? Pitifully, only a few worse, that the patient may discontinue taking the
package inserts specially define the dosing time. This medicine. So it is essential for the members of
critical problem introduces a concept of chronother- MTM to remind themselves to promote medication
apy, which is the optimisation of drug effects and ⁄ or compliance by providing education to the patient
minimisation of adverse drug reactions (ADRs) by regarding the differences between conventional and
timing medications with regard to biological rhythms chronotherapeutic approaches, and pathophysiologic
(1). Numerous sporadic clinical trials have demon- benefits of chronotherapy. This paper focuses on
strated administration time-dependent effects of this respect and aims to describe that better effi-
once-daily medications on therapeutic outcome. So, cacy and lower incidence of ADRs may be
the members of MTM have a lot to relearn about achieved by arranging optimal dosing time of
how to use both old and new once-daily drugs effec- once-daily medications.
ª 2008 The Authors
Journal compilation ª 2008 Blackwell Publishing Ltd Int J Clin Pract, October 2008, 62, 10, 1560–1571

Antigastric-secretion drugs
Proton pump inhibitor (PPI) and H2 receptor antag-
onists (H2RAs) are two major acid-suppressing drugs
used for symptom relief, healing of erosive oesopha-
gitis, 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 dis-
eases (2). This administration schedule is also spe-
cially 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 (rab-
eprazole tablets; Esai Co Ltd, Tokyo, Japan), Prev-
acid (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 trea-
ted by evening dosing (4). Evening dosing of rab-
eprazole (20 mg) normalises more effectively the
total oesophageal exposure and provides signifi-
cantly better control of nocturnal gastro-oesopha-
geal reflux disease than morning dosing (5). One
potential reason for the better efficacy of the eve-
ning 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 con-
secutive 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 acid-
ity and more satisfactory control of 24-h acidity
than dosing at bedtime (22:00 h) and hence is sug-
gested 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.
ª 2008 The Authors
Journal compilation ª 2008 Blackwell Publishing Ltd Int J Clin Pract, October 2008, 62, 10, 1560–1571
Optimal time to take once-daily medicine 1561
Drugs acting on cardiovascular system
In the cardiovascular patient, the focus of chrono-
therapy would be to optimally improve the preven-
tion and treatment of diseases according to circadian
variations and the kinetic and dynamic properties of
drugs. Table 1 lists the optimal dosing time of com-
mon drugs acting on cardiovascular system.
Calcium channel blockers
Several studies compared the efficacies of morning
vs. evening administration of calcium channel block-
ers (CCBs) in patients with essential hypertension.
Administration time-dependent effect on blood pres-
sure (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 cur-
rent package insert of DynaCirc CR (isradipine
controlled release tablets; Reliant Pharmaceuticals,
Inc., Liberty Corner, NJ, USA). A randomised, dou-
ble-blind, placebo-controlled study revealed that the
BP-lowering effect of isradipine sustained release in
18 patients with uncomplicated essential hyperten-
sion (mean age 55 ± 6 years) was regardless of dos-
ing 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 administra-
tion 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 administra-
tion 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
1562 Optimal time to take once-daily medicine

Table 1 Optimal dosing time of common drugs acting on cardiovascular system

Drugs Optimal dosing time Patients

Calcium channel blockers

Isradipine sustained release formulation Evening Hypertensive patients with chronic renal failure
Isradipine sustained release formulation Regardless of time Patients with uncomplicated essential hypertension
Nifedipine GITS Bedtime Patients who are non-responders to the initial 30 mg ⁄ day
dose and in turn receive 60 mg ⁄ day dose or patients
who want to avoid ADRs (e.g. oedema)
Nifedipine GITS Regardless of time Hypertensive patients receiving 30 mg ⁄ day nifedipine GITS
Amlodipine Morning Patients with mild-to-moderate essential hypertension
Nisoldipine extended release Morning Patients with mild-to-moderate essential hypertension
Cilnidipine Bedtime Patients with uncontrollable morning hypertension
Verapamil extended-release (marketed as Covera-HS) Bedtime Angina or hypertensive patients
Diltiazem extended release (marketed as Cardizem LA) Bedtime Angina or hypertensive patients
Angiotensin II receptor blockers
Losartan Uncertain
Ibesartan Regardless of time Patients with uncomplicated, mild-to-moderate
essential hypertension
Olmesartan medoxomil Regardless of time Patients with uncomplicated, mild-to-moderate
essential hypertension
Valsartan Bedtime Non-dipper hypertensive patients
Telmisartan Bedtime Non-dipper hypertensive patients
Telmisartan Morning Young men with mild or moderate essential hypertension
Candesartan cilexetil Awakening Patients with mild-to-moderate essential hypertension
Angiotensin-converting enzyme inhibitors
Benazepril Morning Patients with primary mild-to-moderate hypertension
Perindopril Morning Patients with primary mild-to-moderate hypertension
Quinapril Evening Patients with primary mild-to-moderate hypertension
Ramipril Bedtime Patients with primary mild-to-moderate hypertension
Trandolapril Bedtime Patients with primary mild-to-moderate hypertension
Lisinopril Bedtime Patients with primary mild-to-moderate hypertension
Enalapril Bedtime Patients with primary mild-to-moderate hypertension
Beta-blocker
Metoprolol succinate sustained release Morning Patients with hypertension, angina pectoris or heart failure
Carvedilol Evening Patients who have been treated with first-line antihypertensive
drugs but still had high BP in the morning
Carvedilol phosphate extended release Morning Patients with heart failure, left ventricular dysfunction
following myocardial infarction or hypertension
Propranolol extended release Bedtime Patients with hypertension
Antihyperlipidaemic drugs
Statins with a shorter half-life Evening Patients with hypercholesterolaemia
(i.e. lovastatin, simvastatin and fluvastatin)
Statins with longer half-lives (i.e. fluvastatin Regardless of time Patients with hypercholesterolaemia
extended release, rosuvastatin and atorvastatin)
Pravastatin Evening Patients with hypercholesterolaemia
Atorvastatin Evening Patients undergoing PCI
Ezetimibe Morning Patients with primary hypercholesterolaemia
Ezetimibe ⁄ simvastatin tablet Evening Patients with primary hypercholesterolaemia
Fenofibrate retard Regardless of time Patients with hypertriglyceridaemia
Bezafibrate retard Morning Patients with hypertriglyceridaemia
Doxazosin GITS Morning Patients with grade 1–2 essential hypertension
Regardless of time Patients with benign prostatic hyperplasia
Low-dose aspirin Bedtime Patients who are at risk for a cardiovascular
and ⁄ or cerebrovascular event
Isosorbide mononitrate sustained-release Awakening Patients with angina pectoris
formulation (e.g. Elantan LA, IMDUR)

ª 2008 The Authors

Journal compilation ª 2008 Blackwell Publishing Ltd Int J Clin Pract, October 2008, 62, 10, 1560–1571

Table 1 (continued )
Drugs
Diuretics
Indapamide, hydrochlorothiazide
Torasemide
Once-daily hydrochlorothiazide based
fixed-dose combination
GITS, gastrointestinal therapeutic system; ADRs, adverse drug reactions; PCI, percutaneous coronary intervention; BP, blood pressure.
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 dos-
ing time is not yet defined in prescribing information
for Adalat XL (nifedipine GITS), the dose-depen-
dent enhanced efficacy and the markedly improved
safety profile of bedtime as compared with morning
dosing should be taken into account when prescrib-
ing 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 dos-
ing, but this did not achieve statistical significance
(14). However, a perspective, double-blind, rando-
mised, 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 dos-
ing compared with morning dosing. Nocturnal fall of
BP was greater with morning dosing than with even-
ing dosing (15). Thus, although once daily dosing
time is not yet specially defined in the current pack-
age 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 tim-
ing 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 dos-
ing 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 pre-
ferred for nisoldipine extended release.
ª 2008 The Authors
Journal compilation ª 2008 Blackwell Publishing Ltd Int J Clin Pract, October 2008, 62, 10, 1560–1571
Optimal time to take once-daily medicine 1563
Optimal dosing time Patients
Morning Patients with essential hypertension
Bedtime Patients with essential hypertension
Before 6 pm and preferably Patients with essential hypertension
in the morning
Cilnidipine
An open randomised crossover study in 13 essential
hypertension patients concluded that cilnidipine effi-
cacy was regardless of administration time (17).
However, bedtime but not morning dosing signifi-
cantly 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 eventu-
ally penetrates into the third coat, which osmotically
expands, pushing verapamil out of the tablet at a
constant, fixed rate. According to this design princi-
ple, 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 great-
est 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).
1564 Optimal time to take once-daily medicine
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 (telmi-
sartan tablets; Boehringer Ingelheim, Ridgefield, NJ,
USA), Blopress (candesartan cilexetil tablets; Takeda
Pharmaceutical, Osaka, Japan) and Benicar (olme-
sartan 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) fol-
lowing 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 effi-
cacy of olmesartan medoxomil (20–40 mg) after
12 weeks of morning vs. evening dosing in 18 diur-
nally 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 telmisar-
tan in the morning, as opposed to bedtime dosing,
although the systolic BP values in all the time inter-
vals 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 sig-
nificantly better nocturnal BP regulation following a
12-week therapy with 80 mg telmisartan in 215
patients, mean age 46.4 ± 12.0, with essential hyper-
tension (27). The findings indicate that the dosing
Journal compilation ª 2008 Blackwell Publishing Ltd Int J Clin Pract, October 2008, 62, 10, 1560–1571
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 adminis-
tration 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 candesar-
tan cilexetil (8 mg once daily) was evaluated after
3-month antihypertensive therapy in 60 patients,
mean age 60 ± 6 years, with mild-to-moderate essen-
tial 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 hydro-
chloride tablets), Tritace (ramipril tablets) and MA-

VIK (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 effec-
tively 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 sus-
tained 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
ª 2008 The Authors

significantly more favourable effect on haemodynam-
ics than morning dosing in 30 patients with essential
hypertension stage II (32). Beneficial effects on car-
diovascular morbidity and mortality seen with ram-
ipril 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-dip-
ping BP pattern of the participating cohort of
patients receiving ramipril at bedtime (33).
The optimal dosing time of trandolapril is bed-
time. 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 hyperten-
sion. 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 administra-
tion at 10:00 h, but not at 22:00 h. In addition, BP
was still significantly reduced 24 h after administra-
tion of enalapril at 22:00 h, but not at 10:00 h, indi-
cating the prolonged antihypertensive action of
enalapril after administration at 22:00 h. Thus, night-
time dosing is preferred for enalapril.
Beta-blockers
Beta-blockers are still recommended as first-line ther-
apy 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 carvedi-
lol was observed by Koga et al. (38). Carvedilol, as a
ª 2008 The Authors
Journal compilation ª 2008 Blackwell Publishing Ltd Int J Clin Pract, October 2008, 62, 10, 1560–1571
Optimal time to take once-daily medicine 1565
single dose in the morning or evening in a rando-
mised crossover open-label protocol, was added to
therapy regimen in nine patients who had been trea-
ted with first-line antihypertensive drugs for 4 weeks
but still had high BP in the morning. Evening carv-
edilol administration after 4 weeks significantly sup-
pressed 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 micro-
pump technology that controls the delivery of carv-
edilol 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 approxi-
mately 1.5 h) compared with morning administra-
tion. 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 formu-
lation 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 inten-
tional 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 after-
noon 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.
1566 Optimal time to take once-daily medicine
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 hydroxymethylgluta-
ryl coenzyme A reductase. In general, statins with a
shorter half-life (i.e. lovastatin, simvastatin and flu-
vastatin) are more effective in lowering low-density
lipoprotein-cholesterol (LDL-C) when taken in the
evening, whereas statins with longer half-lives (i.e. flu-
vastatin extended release, rosuvastatin and atorvasta-
tin) have similar lipid-lowering effects when taken
during any time of the day (42–46).
The systemic bioavailability of pravastatin admin-
istered 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 Meva-
lotin (Sankyo), it is also recommended to be taken
once daily at bedtime. New evidence has shown sig-
nificant administration time-dependent influence on
lipid and non-lipid related effects of atorvastatin in
152 patients undergoing PCI. One year clinical fol-
low-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 fre-
quent occurrence of major cardiac events, a low
restenosis rate, a trend towards low pre- and post-
procedural 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 effec-
tive 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
Journal compilation ª 2008 Blackwell Publishing Ltd Int J Clin Pract, October 2008, 62, 10, 1560–1571
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 evi-
dence 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 ⁄ dia-
stolic BP) was observed in patients who was receiv-
ing 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 hyper-
tensive 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. Bed-
time 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, Ger-
many), a long-acting isosorbide mononitrate formu-
lation, 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
ª 2008 The Authors

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 pro-
duces 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
Diuretics are currently recommended as first-line
therapy for the treatment of hypertension. In addi-
tion, they remain an important component in the
treatment of heart failure. Indapamide and hydro-
chlorothiazide should be given in the morning. The
urinary Na ⁄ K ratio in the patients is increased signif-
icantly 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 differ-
ences 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 hydrochlo-
rothiazide 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 (morn-
ing, 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 stan-
dard drug information. Fluoxetine is recommended
ª 2008 The Authors
Journal compilation ª 2008 Blackwell Publishing Ltd Int J Clin Pract, October 2008, 62, 10, 1560–1571
Optimal time to take once-daily medicine 1567
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 combina-
tion 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 hypothyroid-
ism demonstrated that taking the same dose of levo-
thyroxine at bedtime, when compared with that
during morning, might be better. Bedtime dosing
was associated with higher thyroid hormone concen-
trations and lower thyroid stimulating hormone con-
centrations 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 glim-
epiride tablets; GlaxoSmithKline) and Diamicron
MR (gliclazide modified release tablets; Les Labora-
toires Servier, Gidy, France) should be given once
1568 Optimal time to take once-daily medicine
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 symp-
toms and reduce morbidity. Optimal dosing time is
required for some anti-asthma drugs. Bambuterol
(terbutaline prodrug) and montelukast are recom-
mended to be taken at bedtime, as defined in the
current package inserts of Bambec (bambuterol tab-
let; AstraZeneca Pharmaceutical Co Ltd) and Singul-
air (montelukast sodium tablets; Merck & Co,
Cramlington, UK). Evening administration of bam-
buterol in comparison with morning administration
produced enhanced bronchodilator effect at 7 am,
which seemingly was because of the elevated terbuta-
line level maintained during the morning hours fol-
lowing 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). Even-
ing 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 bene-
fit of NSAIDs might be gained by arranging optimal
dosing time. Evening dosing of indomethacin sus-
tained 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 pre-
ferred 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 con-
sistently 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 dos-
ing of ketoprofen controlled release (200 mg)
increased the efficacy without reducing the tolerabil-
ity in patients with osteoarthrosis when compared
with evening dosing. The reduction in the degree of
pain in the afternoon and in the evening was signifi-
Journal compilation ª 2008 Blackwell Publishing Ltd Int J Clin Pract, October 2008, 62, 10, 1560–1571
cantly 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 keto-
profen slow-release tablet (67). Bruguerollea con-
cluded 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. even-
ing) 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 circa-
dian variations at each step, e.g. absorption, distribu-
tion, metabolism and excretion. Interestingly, the
optimal dosing time sometimes is not the time
expected from the perspective of chronopharmacoki-
netics. Aspirin is a representative example. Its bio-
availability in the morning is twice as high as in the
afternoon (70). Taking into account this chrono-
pharmacokinetic 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 exam-
ple, 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, telmi-
sartan, olmesartan medoxomil and candesartan
cilexetil).
ª 2008 The Authors

In clinical practice, members of MTM need to
know the basis for chronotherapy of diseases. For
example, the non-dipper circadian BP pattern repre-
sents 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 pat-
tern 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 chrono-
therapeutic approach is introduced. For instance,
Hermida et al. (72) evaluated the impact on the cir-
cadian pattern of BP by modifying the dosing time
without increasing the number of prescribed drugs.
Results indicate that, in patients with resistant hyper-
tension, 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 com-
bination.
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 exam-
ple, 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).
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 administra-
tion schedule. In order to promote medication com-
pliance, it is essential to provide patient education
regarding differences between conventional and
chronotherapeutic approaches and pathophysiologic
benefits of chronotherapy. For those once-daily med-
ications 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.
ª 2008 The Authors
Journal compilation ª 2008 Blackwell Publishing Ltd Int J Clin Pract, October 2008, 62, 10, 1560–1571
Optimal time to take once-daily medicine 1569
Acknowledgements
Funding for the article is provided by Zhejiang Pro-
vincial Bureau of Education (No. 20070227), Zheji-
ang Medical Association (No. 2007ZYC18) and
Association of Zhejiang Hospital Administration
(No. 2007AZHA-KEB312). 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.
Author contributions
L.-L. Zhu and Q. Zhou put forward the viewpoint
and designed this study; Q. Zhou, X.-F. Yan per-
formed the literature review and data analysis ⁄ inter-
pretation; L.-L. Zhu and Q. Zhou wrote the paper
and S. Zeng was involved in the critical revision of
the article.
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Paper received May 2008, accepted July 2008