A short review of drug–food interactions of medicines treating overactive bladder syndrome
Int J Clin Pharm
A short review of drug-food interactions of medicines treating overactive bladder syndrome
Paweł Pas´ko 0 1 2
Tomasz Rodacki 0 1 2
Renata Domagała-Rodacka 0 1 2
Danuta Owczarek 0 1 2
0 Department of Gastroenterology, Hepatology and Infectious Diseases, Faculty of Medicine, Jagiellonian University Medical College , 31-531 Krako ́w , Poland
1 Department of Food Chemistry and Nutrition, Faculty of Pharmacy, Jagiellonian University Medical College , Krako ́w, Medyczna 9, 30-688 Krako ́w , Poland
2 & Paweł Pas ́ko
Background Overactive bladder syndrome is a condition where one or more of the symptoms such as pollakiuria, urgent need to urinate, nocturia and urinary incontinence is observed. Its prevalence ranges between 7 and 27 % in men and 9-43 % in women. The role of a pharmacist is to educate the patient on medications administration scheme, and drug interactions with particular food or food components. Aim of the review To assess a potential impact of food and fruit juice on the pharmacokinetic and therapeutic effects of medications used in treating overactive bladder syndrome. This information will enhance pharmaceutical care and is vital and helpful for pharmacists counseling their patients. Method In order to gather information on interactions of medications employed in bladder dysfunctions, the English language reports published in the PubMed, Embase, Cochrane and CINAHL database over the years 1996-2015 were studied. Additionally, other resources, namely drugs.com, Medscape, UpToDate, Micromedex, Medical Letter, as well as Stockley Drugs Interaction electronic publication were included in the study. The analysis also covered product
Anticholinergic drugs; Drugs-food interactions; Overactive bladder syndrome; Review; Urinary incontinence
data sheets for particular medicinal products. Results Meals
and the consumption of grapefruit juice were found to exert
a diversified effect on the pharmacokinetics of drugs
employed in overactive bladder syndrome therapy. Neither
tolterodine, nor mirabegron interact with food and citrus
fruit juice, whereas darifenacin, fesoterodine, oxybutynin
and solifenacin do interact with grapefruit and others citrus
fruit juice. The effects of such interactions may potentially
be negative to patients. Trospium absorption is
significantly decreased by food. Conclusion For selected
medicines used in treating bladder dysfunctions food and
grapefruit juice consumption may significantly affect
efficacy and safety of the therapy. All information on the topic
is likely to enhance the quality of pharmaceutical care.
Impacts on practice
• It is important for optimal pharmaceutical care that the
pharmacist has knowledge about interactions between
food and citrus fruit juice and medicines to treat
• Of the medicines to treat bladder dysfunction, only the
effect of trospium was found to be significantly affected
by food therefore the medication should be
administered on an empty stomach.
• The majority of medicines to treat bladder dysfunction
may potentially interact with grapefruit and other citrus
fruit juice, and the effects of such interactions may be
negative for patients.
Overactive bladder syndrome (OAB) is a condition where
one or more of the symptoms such as pollakiuria, urgent
need to urinate, nocturia and urinary incontinence [
observed. The syndrome may coexist with other diseases,
such as diabetes, Parkinson’s disease, multiple sclerosis,
stroke or spinal cord injuries, or be of idiopathic nature [
Its recorded incidence ranges between 7 and 27 % in
males, and from 9 to 43 % in females [
]. According to the
international population-based study performed in Europe
and Canada, 12.8 % of females and 10.8 % of males suffer
from OAB [
]. Especially urinary incontinence affects
women more frequently. The frequency and severity of all
symptoms tend to increase with age, and is two times more
common in individuals over 65 years of age, compared to
subjects below 45 [
]. OAB is a condition that markedly
deteriorates quality of life in patients . Muscular and
neural factors play a significant role in OAB
]. The main group of drugs employed in OAB
therapy includes the muscarinic receptor antagonists. The
medicines inhibit the effect of acetylcholine on the
muscular coat of the urinary bladder [
]. Adverse effects of
anticholinergic drugs include xerostomia, constipation,
visual disturbances, and rarely arrhythmia [
such as mirabegron, a b3 receptor agonist, or botulinum
toxin (in intradetrusor injections) have been introduced
There are some recent developments around the
treatment of bladder dysfunctions [
]. New pharmacological
targets can be found at the level of the urothelium, detrusor
muscles, autonomic and afferent pathways, spinal cord and
brain. Selected K? ion channels potentially may provide
therapeutic targets for bladder diseases. In the urinary
bladder, activated K? channels, in particular the
largeconductance Ca2?-activated K? channels (BK), prevents
excessive excitability and contractility of urinary bladder
smooth muscle. The BK channel seems to play a significant
role in reducing both cholinergic- and purinergic-induced
contractility and BK channel function alterations by
specific drugs have been suggested to contribute to OAB
occurrence. Activity in the serotonergic pathway can
enlarge urine storage capability by facilitating the vesical
sympathetic reflex pathway and inhibiting the
parasympathetic voiding pathway. Thus, 5-HT receptor antagonists
and reuptake inhibitors represent important targets for
developing new OAB treatments. Alfa 1- and alfa
2-adrenoceptors seem to be also involved in micturition
control. In addition, opioid receptors, and GABA-ergic
systems open a wide range of possibilities. Recently, a
relaxation of human detrusor smooth muscle induced by
phosphodiesterase type 5 inhibitors with cGMP-,
cAMPand K? channel-dependent signaling pathways involved
have been reported. Nociceptin/orphanin FQ receptor
agonists have been also suggested to be potentially
effective new drugs for treating neurogenic urinary
It is the pharmacist’s role to educate patients about
proper medication administration schemes, and not to limit
advice to drug–drug interactions, but to cover also drug–
food and drug–particular food component interactions [
The appropriate mode of taking medicines is important for
optimizing pharmacotherapy [
]. Knowledge about drug–
food interactions is important for the safety and
optimization of pharmacotherapy for bladder dysfunctions. A
database on this topic will be helpful to pharmacists when
counseling their patients, as a necessary element of
Aim of the review
In view of the increase in use of medicines for the
dysfunctional bladder, it is important to investigate potential
effects that food and fruit juice consumption may have on
the pharmacokinetics and therapeutic effect of such
Four databases, PubMed, Embase, Cochrane and CINAHL
covering reports from 1996 to 2015 have been searched
with the following key words and phrases: drugs name for
bladder dysfunctions treatments, urinary incontinence,
food, fruit juices, grapefruit, pharmacokinetics and
pharmacodynamics, plus drugs–food interaction. The search
was limited to English papers and the reference lists quoted
therein. Additionally, other resources such as drugs.com,
Medscape, UpToDate, Micromedex, Medical Letter, as
well as the electronic Stockley Drugs Interaction were also
searched. Specific medicinal product datasheets were also
included into analysis. Duplicated data were excluded. The
search process is presented in Fig. 1. With all the materials
collected, a critical review was carried out and the result is
presented as a mini-review. Important information on
drug–food interaction are presented in a tabular form (see
Table 1). Practical recommendations for pharmacists and
The Cochrane library
Searching other resources
Studies included *
drugs.com Micromedex UpToDate Medscape
Interaction data sheets
Data included in synthesis
*The reference lists of relevant articles were searched for other possible relevant trials.
physicians how to solve food interaction problems for a
particular drug are contained therein.
Results and discussion
Skerjanec et al. indicated that a single dose of darifenacin
administered as extended-release tablets (30 mg) together
with a high-fat meal not only did not affect the drug
bioavailability, but resulted in a 22 % increase in Cmax
whereas Tmax was prolonged by 3.3 h. Similarly, when
administered in a multiple dose over 10 days, no
foodrelated effect on its pharmacokinetic parameters was noted.
Additionally, none of the adverse effects had increased,
neither with respect to their number, nor intensity, for the
drug administered with meals. Therefore, it can be either
taken with food or on an empty stomach [
Darifenacin is metabolized in the liver by CYP 3A4 and
2D6 isoenzymes. Supposedly, for that reason a potential
risk of drug–grapefruit juice interaction was reported, as
the latter is a known CYP 3A4 inhibitor. Moreover,
inhibited darifenacin metabolism might result in intensified
adverse effects. However, the clinical importance of the
interaction seems to be minor [
Malhotra et al.  investigated the effect of food, namely
high-fat, high-calorie breakfast, on the pharmacokinetics of
5-hydroxymethyl tolterodine (5-HMT), the main active
metabolite of fesoterodine. The study included 16 healthy
males, who were administered a single 8 mg dose of the
drug. High-fat food resulted in insignificant increase in
AUC, whereas Cmax of the active metabolite increased by
approximately 19 %. The remaining pharmacokinetic
parameters, such as Tmax or drug elimination parameters,
did not change.
5-HMT is metabolized to carboxyl in a process
involving CYP2D6 and CYP3A4 enzymes,
carboxy-N-diisopropyl and N-diisopropyl metabolites, which do not have
significant pharmacological activity. The respective mean
values for Cmax and AUC were respectively found to be 1.7
and twice higher in individuals showing a weak
metabolizing activity of CYP2D6, as compared to subjects with a
high metabolic potency of the isoenzyme [
]. For this
reason, Malhorta et al. [
] studied the pharmacokinetic
parameters of a single administration of fesoterodine given
as extended-release tablets at doses of 4, 8 and 12 mg to 24
healthy volunteers, 16 of whom showed high metabolic
potency, and 8 low metabolic potency of CYP2D6.
Additionally, for the dose of 8 mg, the effect of high-calorie and
high-fat food on the pharmacokinetics of 5-HMT drug was
studied; AUC and Cmax were found to increase by 12 and
29 %, respectively, due to consumed food, though such
changes were not considered to be of clinical significance.
Similarly, none meal-related effect was demonstrated for
CYP2D6 activity. 5-HMT Cmax and AUC were
approximately two times higher in individuals with low CYP2D6
metabolic potency, yet the activity of the isoenzyme was
found to affect neither Tmax, renal clearance, nor half-life
of the medication. Only for doses above 8 mg, an increase
in the prevalence of xerostomia was observed, though the
changes were mild and well-tolerated by the study
participants. Based on the above results, the drug can be taken
irrespectively of meals.
The use of moderate CYP3A4 inhibitors, i.e. grapefruit
juice and other grapefruit-based products, may result in
increased serum concentration levels of the active
metabolite of fesoterodine 5-HMT, which is partially
metabolized by the isoenzyme. Since 5-HMT is also
metabolized by CYP2D6, the clinical importance of the
interaction may be higher in patients with a low metabolic
potency for CYP2D6 isoenzyme, i.e. approximately for
7 % of Caucasians, and below 2 % of Asians and people of
African descent, in whom the CYP3A4-dependent
metabolic pathway is more significant for the further drug
processing in the body. Thus, increased fesoterodine
activity should be taken into account whenever the drug
administration coincides with grapefruit elements in the
patients diet. Such adverse effects of the drug may manifest
itself by irregular heartbeat, blurred vision, difficult
urination, xerostomia, headache, somnolence, dizziness,
gastrointestinal problems or constipation [
Sathyan et al. [
] investigated the effect of food on
bioavailability of oxybutynin (15 mg) administered as a
single extended-release dose to 50 healthy volunteers.
Their meal consisted of high-fat breakfast, and they studied
the effect on the drug pharmacokinetics and its active
metabolite. No significant food-related effect on the above
parameters was demonstrated.
Lukkari et al. [
] performed a similar study on the
effect of high-fat food on the pharmacokinetic properties of
oxybutynin and N-deethyloxybutynin, its active metabolite.
The medication was administered as a single 10 mg dose in
extended-release tablets to a group of 23 healthy
volunteers, including 12 women and 11 men. High-fat breakfast
was found not to change oxybutynin AUC, though it
triggered a significant increase in AUC, reportedly by
approximately 20 %, for its active metabolite. The food
doubled the increase in Cmax for oxybutynin and
N-deethyloxybutynin alike. Significantly prolonged Tmax
for the metabolite of the drug was attributed to meal.
Though no significant differences in the prevalence of
adverse effects was observed, for the medication taken
after a meal, a decrease in saliva secretion was found to be
higher than when the drug was administered on an empty
Lukkari et al. [
] investigated the effect of food on the
prevalence of drug related adverse effects. The authors
confirmed that a meal resulted in a significant increase in
Cmax both for the drug and its metabolite, and increased
AUC for N-deethyloxybutynin. However, for the
medication administered 2 h after a meal, the amount of
produced saliva was observed to significantly decrease, as
compared to oxybutynin administration on an empty
For oxybutynin given as a solution, a meal resulted in
prolonged Tmax and 25 % increase in AUC [
Observations as above, give ground to surmise that as
food-related changes in the drug pharmacokinetics were
of no clinical significance, the medication may be
administered irrespectively of meals. Nevertheless,
administration of oxybutynin, especially in its
extendedrelease form, one hour before a meal allows for achieving
the drug concentration value that shows only slight
variations between the employed doses; this may be of
importance in improved tolerance of the medications in
patients who suffer from limited saliva secretion during
As the oxybutynin is metabolized by CYP 3A4, caution
is recommended when simultaneously consuming
grapefruit juice, a known inhibitor of the enzyme. Simultaneous
consumption of oxybutynin and grapefruit juice may
potentially increase the risk of adverse effects associated
with the medication. The clinical significance of the
interaction remains unknown [
Uchida et al. [
] studied the effect of food on the
pharmacokinetics of solifenacin (10 mg). Twenty-three healthy
men were divided into two groups. The first group received
the drug on an empty stomach together with 180 ml of
water, while the second group took the medication 5 min
following a standard high-fat meal of 1000 kcal, with
approximately 50–60 % of the total calories originating
from fats, 15 % from proteins and approximately 25 %
from carbohydrates. No changes were noted in the
pharmacokinetic parameters of the medication administered
with the meal.
Solifenacin is metabolized in the liver, in the process
where CYP3A4 isoenzyme is predominantly involved.
Thus, grapefruit juice which inhibits the isoenzyme activity
causes blood-solifenacin concentration to increase, and
may increase the risk of toxicity [
Ollson et al. [
] investigated the effect of medium-fat
breakfast on the pharmacokinetic parameters of
tolterodine and its active metabolite 5-hydroxymethyl
tolterodine (5-HMT). To meet the study objective 23 healthy
volunteers with normal CYP2D6 isoenzyme activity were
administered a single dose of tolterodine, namely 2 mg of
immediate-release form (IR). For tolterodine, the meal
resulted in increased AUC and Cmax by 53 and 49 %,
respectively, while for the active metabolite of 5-HMT,
food was found not to change the drug pharmacokinetic
parameters. In spite of significant alterations in
bioavailability of tolterodine, its clinical effect was not
In another study by Ollson et al. [
] the effect of food
on the pharmacodynamics of tolterodine administered
2 9 40 mg as extended-release capsules (ER) and its
metabolite 5-HMT was studied. Seventeen healthy
volunteers, 3 women and 14 men, of whom one male
demonstrated a decreased activity of CYP2D6 isoenzyme,
received the medicine either on an empty stomach, or after
a high-fat meal. No effect of food on the bioavailability of
the ER form of the drug was observed.
Food, especially high-fat products, cause Cmax and AUC of
trospium to decrease by approximately 15–20 % [
Doroshyenko et al. [
] reported twenty-four healthy
males who have received two dragees of trospium at the
dose of 20 mg either on an empty stomach, or after a
highfat meal. In consequence of administering the drug with a
meal, a significant decrease in Cmax occurred, specifically
from 9.2 ng/ml on an empty stomach to 1.3 ng/ml after a
meal on average. AUC of the drug was reduced by over
70 %, from 87.2 ng 9 h/ml on an empty stomach to
20.1 ng 9 h/ml after a meal. The food resulted in
decreasing Tmax from 5 h on an empty stomach to 3.3 h
after a meal [
Administration of trospium as extended-release capsules
together with a high-fat meal caused a drop in AUC and
Cmax by o 35 and 60 %, respectively [
Taking trospium with a high-fat meal resulted in a
decrease in the drug absorption, with a decrease of the
AUC and Cmax parameters by 70–80 %, as compared to its
administration on an empty stomach [
]. This is also
confirmed by the drugs.com database [
b3 adrenoceptor agonist
Lee et al. [
] investigated the effect of high-fat and
lowfat breakfast on the pharmacokinetic parameters of
mirabegron taken as OCAS tablets (orally controlled
absorption system) administered at doses of 50 and 100 mg to 38
healthy men, either 30 min after a meal, or on an empty
For a high-fat meal and the drug given at the dose of
50 mg, a 45 % decrease was noted in Cmax and a 17 %
drop in AUC. The use of mirabegron at the dose of 100 mg
with the same meal resulted in decreasing Cmax and AUC
by 39 and 18 %, respectively.
A low-fat meal also resulted in a decrease in Cmax and
AUC; at a 50 mg dose by 75 % and 51 %, respectively,
and at the dose of 100 mg by 64 and 47 %.
Changes in Tmax were independent of the amount of fat
in the meal; in general, food resulted in prolonged Tmax that
by 0.9 h and 1.5–2 h for the dose of 50 and 100 mg,
The use of mirabegron as OCAS tablets together with
a meal resulted in significant changes in the
pharmacokinetic parameters that were independent of the dose,
but dependent on the meal fat content. A low-fat meal
triggered a significantly higher reduction in
bioavailability of the drug as compared to a high-fat meal. Such
significant differences in the drug pharmacokinetics
contributed to the meal effect are not, however,
important with respect to the drug effectiveness, and therefore
mirabegron may be administered irrespectively of meals
Overall it is clear that there are gaps in the knowledge
on interaction with medicines for bladder dysfunction,
especially with respect to the consequences of food–drug
interactions. Data to guide clinical recommendations is
scarce. Heuberger [
] and Pas´ko et al. [
several reason for that, such as measurement difficulties,
hardly available proper samples, as well as the lack of
study framework and little research interest. Few
reserachers acknowledge the importance of the problem, its
clinical significance, cost, and overall impact on the
An appropriate mode of administering medications
employed in overactive bladder syndrome and other lower
urinary tract dysfunctions may result in limiting the
occurrence of adverse effects and optimal use of the lowest
possible doses of the drugs. As far as food is concerned most
drugs can be taken irrespectively of meals. Only trospium is
to be taken either on empty stomach, or an hour before the
meal. As most of the described medications, such as
darifenacin, fesoterodine, oxybutynin, and solifenacin, are
metabolized in the liver by CYP 3A, their potential to
interact with grapefruit juice cannot be neglected. As
reported by Mazi-Kotwal et al. [
] and Baily et al. [
clinical effect of such interaction was determined as
‘moderate’ or ‘intermediate’. Specific medicinal
substances, or supplements, consumed with food may
significantly affect the efficacy and safety of the therapy. Gaps in
knowledge on interactions especially with respect to the
consequences of food–drug interactions are evident.
Conflicts of interest Authors have no conflict of interest to report.
Open Access This article is distributed under the terms of the Creative
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In patients manifesting disturbances of saliva secretion during therapy,
taking the drug 0.5–1 h prior to a planned meal is recommended
Exercise caution while consuming grapefruit juice during therapy
Grapefruit juice should not be consumed during solifenacin therapy
May be taken irrespectively of a meal
To be taken 1 h prior to a meal or on an empty stomach
May be taken irrespectively of a meal
1. Gormley EA , Lightner DJ , Burgio KL , Chai TC , Clemens JQ , Culkin DJ , et al. Diagnosis and treatment of overactive bladder (non-neurogenic) in adults: AUA/SUFU guideline . Linthicum: American Urological Association Education and Research Inc.; 2014 .
2. Patraa PB , Patrab S. Research findings on overactive bladder . Curr Urol . 2014 ; 8 : 1 - 21 .
3. Wolff GF , Kuchel GA , Smith PP . Overactive bladder in the vulnerable elderly . Res Rep Urol . 2014 ; 6 : 131 - 8 .
4. Armstrong C. AUA releases guideline on diagnosis and treatment of overactive bladder . Am Fam Physician . 2013 ; 87 : 800 - 3 .
5. Epstein BJ , Gums JG , Molina E . Newer agents for the management of overactive bladder . Am Fam Physician . 2006 ; 74 : 2061 - 8 .
6. Andersson KE . Drug therapy of overactive bladder-what is coming next? Korean J Urol . 2015 ; 56 : 673 - 9 .
7. Cerruto MA , Asimakopoulos AD , Artibani W , Del Popolo G , La Martina M , Carone R , et al. Insight into new potential targets for the treatment of overactive bladder and detrusor overactivity . Urol Int . 2012 ; 89 : 1 - 8 .
8. Andersson KE . New pharmacologic targets for the treatment of the overactive bladder: an update . Urology . 2004 ; 63 : 32 - 41 .
9. Kaur G , Gan YL , Phillips CL , Wong K , Saini B. Chronotherapy in practice: the perspective of the community pharmacist . Int J Clin Pharm . 2016 ; 38 : 171 - 82 .
10. Pawłowska I , Pawłowski L , Kocic´ I, Krzy z_aniak N. Clinical and conventional pharmacy services in Polish hospitals: a national survey . Int J Clin Pharm . 2016 ; 38 : 271 - 9 .
11. Skerjanec A. The clinical pharmacokinetics of darifenacin . Clin Pharmacokinet . 2006 ; 45 : 325 - 50 .
12. Mazi-Kotwal N , Seshadri M. Drug interactions with grapefruit juice . BJMP . 2012 ; 5 : a538 .
13. Emselex 7.5 mg prolonged release tablets-Summary of Product Characteristics [Internet] . Medicines.org.uk; 2015 [cited 2016 February 15 ]. https://www.medicines.org.uk/emc/medicine/ 28307.
14. Malhotra B , Sachse R , Wood N. Influence of food on the pharmacokinetic profile of fesoterodine . Int J Clin Pharmacol Ther . 2009 ; 47 : 384 - 90 .
15. Toviaz 4 mg prolonged-release tablets-Summary of Product Characteristics [Internet] . Medicines.org.uk; 2014 [cited 2016 February 15 ]. https://www.medicines.org.uk/emc/medicine/209 28.
16. Malhotra B , Guan Z , Wood N , Gandelman K. Pharmacokinetic profile of fesoterodine . Int J Clin Pharmacol Ther . 2008 ; 46 : 556 - 63 .
17. Sathyan G , Hu W , Gupta SK . Lack of effect of food on the pharmacokinetics of an extended-release oxybutynin formulation . J Clin Pharmacol . 2001 ; 41 : 187 - 92 .
18. Lukkari E , Castre` n-Kortekangas P , Juhakoski A , Lo¨yttyniemi E, Aranko K , Neuvonen PJ . Effect of food on the bioavailability of oxybutynin from a controlled release tablet . Eur J Clin Pharmacol . 1996 ; 50 : 221 - 3 .
19. Lukkari E , Aranko K , Juhakoski A , Hakonen T , Neuvonen PJ . Effect of time interval between food and drug ingestion on the absorption of oxybutynin from a controlled-release tablet . Pharmacol Toxicol . 1997 ; 81 : 31 - 4 .
20. Oxybutynin-FDA prescribing information [Internet] . Drugs .- com; 2016 [cited 2016 February 15 ]. https://www.drugs.com/pro/ oxybutynin.html.
21. Deepalakshmi M , Arun KP , Ahuja S. Grapefruit and medications may be a deadly mix-an overview . J Pharm BioSci . 2014 ; 3 : 80 - 4 .
22. Uchida T , Krauwinkel WJ , Mulder H , Smulders RA . Food does not affect the pharmacokinetics of solifenacin, a new muscarinic receptor antagonist: results of a randomized crossover trial . Br J Clin Pharmacol . 2004 ; 58 : 4 - 7 .
23. Felicilda-Reynaldo RF . A review of anticholinergic medications for overactive bladder symptoms . Medsurg Nurs . 2013 ; 22 : 119 - 23 .
24. Olsson B , Brynne N , Johansson C , Arnberg H . Food increases the bioavailability of tolterodine but not effective exposure . J Clin Pharmacol . 2001 ; 41 : 298 - 304 .
25. Olsson B , Szamosi J . Food does not influence the pharmacokinetics of a new extended release formulation of tolterodine for once daily treatment of patients with overactive bladder . Clin Pharmacokinet . 2001 ; 40 : 135 - 43 .
26. Trospium chloride 20 mg film-coated tablets-Summary of Product Characteristics [Internet] . Medicines.org.uk; 2015 [cited 2016 February 15 ]. https://www.medicines.org.uk/emc/medicine/ 31208.
27. Doroshyenko O , Jetter A , Odenthal KP , Fuhr U. Clinical pharmacokinetics of trospium chloride . Clin Pharmacokinet . 2005 ; 44 : 701 - 20 .
28. Baxter K , Preston CL , editors. Stockley's drug interaction. 10th ed . London: Pharmaceutical Press; 2013 .
29. Trospium-FDA prescribing information [Internet] . Drugs.com; 2015 [cited 2016 February 15 ]. https://www.drugs.com/pro/tros pium-chloride.html.
30. Lee J , Zhang W , Moy S , Kowalski D , Kerbusch V , van Gelderen M, et al. Effects of food intake on the pharmacokinetic properties of mirabegron oral controlled-absorption system: a single-dose, randomized, crossover study in healthy subjects . Clin Ther . 2013 ; 35 : 333 - 41 .
31. Betmiga 25 mg prolonged-release tablets-Summary of Product Characteristics [Internet] . Medicines.org.uk; 2016 [cited 2016 February 15 ]. https://www.medicines.org.uk/emc/medicine/27429.
32. Heuberger R . Polypharmacy and food-drug interactions among older persons: a review . J Nutr Gerontol Geriatr . 2012 ; 31 : 325 - 403 .
33. Pas´ko P, Rodacki T , Domagała-Rodacka R , Owczarek D . Interactions between medications employed in treating benign prostatic hyperplasia and food-a short review . Biomed Pharmacother . 2016 ; 83 : 1141 - 5 .
34. Bailey DG , Dresser G , Arnold JMO . Grapefruit-medication interactions: forbidden fruit or avoidable consequences? CMAJ. 2013 ; 185 : 309 - 16 .