SIDE EFFECTS
The Phase 2 and 3 clinical trial program for DETROL
included 2,049 patients who were treated with DETROL (N=1,619)
or placebo (N=430). No differences in the safety profile
of tolterodine were identified based on age, gender, race,
or metabolism. Four Phase 3, 12-week, controlled clinical
studies form the basis for the main evaluation of safety
and the results are summarized below.
Adverse events considered to be treatment-related were dry
mouth, dyspepsia, headache, constipation, and xerophthalmia.
Dr. mouth, constipation, abnormal vision (accommodation
abnormalities), urinary retention, and xerophthalmia are
expected side effects of antimuscarinic agents.
Dry mouth was the most frequently, reported adverse event
for patients treated with DETROL 2 mg twice daily in the
Phase 3 clinical studies, occurring in 39.5% of patients
treated with DETROL and 15.9% of placebo treated patients;
0.8% of patients treated with DETROL discontinued treatment
due to dry mouth.
The frequency of discontinuation due to adverse events was
highest during the first 4 weeks of treatment. Eight percent
of patients treated with DETROL 2 mg twice daily discontinued
treatment due to adverse events. The most common adverse
events leading to discontinuation were dizziness and headache.
The following table lists the adverse events reported in
1% or more of the patients treated with DETROL 2 mg twice
daily in the 12-week studies. The adverse events are reported
regardless of causality.
Incidence % of Adverse Events Reported
In > 1 % of Patients Treated with DETROL (2 mg b.i.d.)
in 12-week Phase 3 Clinical Studies
|
|
Adverse Event
|
DETROL
2 mg
bid
N= 474
|
Placebo
N= 176
|
| %
Patients Reporting Adverse Events |
75.5
|
77 .8
|
| %
Patients Reporting serious Adverse Events |
3.7
|
3.4
|
| %
Patients Discontinuing due to Adverse Events |
8.0
|
5.7
|
| Autonomic
Nervous |
dry
mouth |
39.5
|
15.9
|
| General |
back
pain |
2.7
|
3.4
|
| chest
pain |
3.4
|
1.7
|
| fatigue
|
6.8
|
7.4
|
| headache
|
11.0
|
7.4
|
| influenza-like
symptoms |
4.4
|
6.3
|
| fall
|
1.3
|
0.6
|
| Central/
Peripheral Nervous |
paresthesia
|
1.1
|
0.6
|
| vertigo/dizziness
|
8.6
|
9.1
|
| Gastrointestinal |
abdominal
pain |
7.6
|
6.3
|
| constipation
|
6.5
|
4.5
|
| diarrhea
|
4.0
|
6.3
|
| dyspepsia
|
5.9
|
1.7
|
| flatulence
|
1.3
|
0.6
|
| nausea
|
4.2
|
5.7
|
| vomiting/nausea
|
1.7
|
0.6
|
| Respiratory
|
bronchitis
|
2.1
|
0.6
|
| coughing
|
2.1
|
1.7
|
| pharyngitis
|
1.5
|
2.3
|
| rhinitis
|
1.1
|
1.1
|
| sinusitis
URI
|
1.1
|
5.7
|
| Urinary |
urinary
dysuria |
2.5
|
4.0
|
| micturition
frequency |
1.1
|
1.7
|
| retention/mict
dis |
1.7
|
2.8
|
| UTI
|
5.5
|
7.4
|
| Skin/Appendages |
pruritus
|
1.3
|
1.1
|
| rash/erythema
|
1.9
|
2.8
|
| skin
dry |
1.7
|
0.6
|
| Musculoskeletal
|
arthralgia
|
2.3
|
2.8
|
| Vision
|
vision
abnormal (including) |
|
|
| accommodation
|
4.7
|
4.0
|
| xerophthalmia
|
3.8
|
1.7
|
| Psychiatric
|
nervousness
|
1.1
|
0.6
|
| somnolence
|
3.0
|
1.7
|
| Metabolic/
Nutritional |
weight
gain |
1.5
|
1.1
|
| Cardiovascular
|
hvpertension
|
1.5
|
0.6
|
| Resistance
Mechanism |
infection |
2.1
|
1.1
|
| |
infection
fungal |
1.1
|
0.0
|
Abbreviations: URI = upper respiratory infection, UTI =
urinary tract infection, mict dis = micturition disorders.
DRUG INTERACTIONS
Cytochrome P450 3A4 Inhibitors: Pharmacokinetic
studies with patients concomitantly receiving cytochrome
P450 3A4 inhibitors, such as macrolide antibiotics (erythromycin
and clarithromycin) or antifungal agents (ketoconazole,
itraconazole, and miconazole), have not been performed.
Patients receiving cytochrome P450 3A4 inhibitors should
not receive doses of DETROL greater than 1 mg twice daily.
Drug-Laboratory-Test Interactions
Interactions between tolterodine and laboratory
tests have not been studied.
Drug-Drug Interactions
Fluoxetine: Fluoxetine
is a selective serotonin reuptake inhibitor and a potent
inhibitor of cytochrome P450 2D6 activity. In a study to
assess the effect of fluoxetine on the pharmacokinetics
of tolterodine and its metabolites, it was observed that
fluoxetine significantly inhibited the metabolism of tolterodine
in extensive metabolizers, resulting in a 4.8-fold increase
in tolterodine A.C. There was a 52% decrease in Cmax and
a 20% decrease in AUC of the S-hydroxymethyl metabolite.
Fluoxetine thus alters the pharmacokinetics in patients
who would otherwise be extensive metabolizers of tolterodine
to resemble the pharmacokinetic profile in poor metabolizers.
The sums of unbound serum concentrations of tolterodine
and the 5-hydroxymethyl metabolite are only 25% higher during
the interaction. No dose adjustment is required when DETROL
and fluoxetine are coadministered.
Other Drugs Metabolized by Cytochrome P450 2D6:
Tolterodine is not expected to influence the pharmacokinetics
of drugs that are metabolized by cytochrome P450 2D6, such
as flecainide, vinblastine, carbamazepine, and tricyclic
antidepressants; however, the potential effect of tolterodine
on the pharmacokinetics of these drugs has not been formally
evaluated.
Warfarin: In healthy volunteers,
coadministration of tolterodine 2 mg twice daily for 7 days
and a single 25-mg dose of warfarin on day 4 had no effect
on prothrombin time, Factor VII suppression, or on the pharmacokinetics
of warfarin.
Oral Contraceptives: Tolterodine
2 mg twice daily had no effect on the pharmacokinetics of
an oral contraceptive ethinyl estradiol 30 ug/levonorgestrel
150 ug as evidenced by the monitoring of ethinyl estradiol
and levonorgestrel over a 2-month cycle in healthy female
volunteers.
Diuretics: Coadministration of
tolterodine up to 4 mg twice daily for up to 12 weeks with
diuretic agents, such as indapamide, hydrochlorothiazide,
triamterene, bendroflumethiazide, chlorothiazide, methylchlorothiazide,
or furosemide, did not cause any adverse electrocardiographic
(ECG effects).
|
|
