12.3 Pharmacokinetics
The pharmacokinetics of tamsulosin hydrochloride have been evaluated in adult
healthy volunteers and patients with BPH after single and/or multiple
administration with doses ranging from 0.1 mg to 1 mg.
Absorption
Absorption of tamsulosin hydrochloride from
tamsulosin hydrochloride capsules 0.4 mg is essentially complete (>90%)
following oral administration under fasting conditions. Tamsulosin hydrochloride
exhibits linear kinetics following single and multiple dosing, with achievement
of steady-state concentrations by the fifth day of once-a-day dosing.
Effect of Food
The time to maximum
concentration (T
max) is reached by four to five hours
under fasting conditions and by six to seven hours when tamsulosin hydrochloride
capsules are administered with food. Taking tamsulosin hydrochloride under
fasted conditions results in a 30% increase in bioavailability (AUC) and 40% to
70% increase in peak concentrations (C
max) compared to
fed conditions (Figure 1).
Figure 1 Mean Plasma
Tamsulosin Hydrochloride Concentrations Following Single-Dose Administration of
Tamsulosin Hydrochloride Capsules 0.4 mg Under Fasted and Fed Conditions (n=8)
The effects of food on the pharmacokinetics of tamsulosin hydrochloride are
consistent regardless of whether a tamsulosin hydrochloride capsule is taken
with a light breakfast or a high-fat breakfast (Table 2).
Table 2 Mean (± S.D.) Pharmacokinetic Parameters Following Tamsulosin
Hydrochloride Capsules 0.4 mg Once Daily or 0.8 mg Once Daily with a Light
Breakfast, High-Fat Breakfast or Fasted
C
min = observed minimum concentration
C
max = observed maximum tamsulosin hydrochloride plasma
concentration
T
max = median time-to-maximum
concentration
T
1/2 = observed half-life
AUC
τ = area under the tamsulosin hydrochloride plasma time curve
over the dosing interval
Distribution
The mean steady-state apparent volume of
distribution of tamsulosin hydrochloride after intravenous administration to ten
healthy male adults was 16 L, which is suggestive of distribution into
extracellular fluids in the body.
Tamsulosin hydrochloride is extensively
bound to human plasma proteins (94% to 99%), primarily alpha
1 acid glycoprotein
(AAG), with linear binding over a wide concentration range (20 to 600 ng/mL).
The results of two-way
in vitro studies indicate that
the binding of tamsulosin hydrochloride to human plasma proteins is not affected
by amitriptyline, diclofenac, glyburide, simvastatin plus simvastatin-hydroxy
acid metabolite, warfarin, diazepam, propranolol, trichlormethiazide, or
chlormadinone. Likewise, tamsulosin hydrochloride had no effect on the extent of
binding of these drugs.
Metabolism
There
is no enantiomeric bioconversion from tamsulosin hydrochloride [R(-) isomer] to
the S(+) isomer in humans. Tamsulosin hydrochloride is extensively metabolized
by cytochrome P450 enzymes in the liver and less than 10% of the dose is
excreted in urine unchanged. However, the pharmacokinetic profile of the
metabolites in humans has not been established. Tamsulosin is extensively
metabolized, mainly by CYP3A4 and CYP2D6, as well as via some minor
participation of other CYP isoenzymes. Inhibition of hepatic drug-metabolizing
enzymes may lead to increased exposure to tamsulosin [
see Warnings and Precautions (5.2) and Drug Interactions
(7.1)]. The metabolites of tamsulosin hydrochloride undergo extensive
conjugation to glucuronide or sulfate prior to renal excretion.
Incubations with human liver microsomes showed no evidence of clinically
significant metabolic interactions between tamsulosin hydrochloride and
amitriptyline, albuterol (beta agonist), glyburide (glibenclamide) and
finasteride (5alpha-reductase inhibitor for treatment of BPH). However, results
of the in vitro testing of the tamsulosin hydrochloride interaction with
diclofenac and warfarin were equivocal.
Excretion
On administration of the radiolabeled dose of tamsulosin
hydrochloride to four healthy volunteers, 97% of the administered radioactivity
was recovered, with urine (76%) representing the primary route of excretion
compared to feces (21%) over 168 hours.
Following intravenous or oral
administration of an immediate-release formulation, the elimination half-life of
tamsulosin hydrochloride in plasma ranged from five to seven hours. Because of
absorption rate-controlled pharmacokinetics with tamsulosin hydrochloride
capsules, the apparent half-life of tamsulosin hydrochloride is approximately 9
to 13 hours in healthy volunteers and 14 to 15 hours in the target population.
Tamsulosin hydrochloride undergoes restrictive clearance in humans, with
a relatively low systemic clearance (2.88 L/h).
Special Populations
Pediatric Use
Tamsulosin hydrochloride capsules are not indicated for use in
pediatric populations [
see Use in Specific Populations
(8.4)].
Geriatric (Age) Use
Cross-study comparison of tamsulosin hydrochloride capsules overall
exposure (AUC) and half-life indicates that the pharmacokinetic disposition of
tamsulosin hydrochloride may be slightly prolonged in geriatric males compared
to young, healthy male volunteers. Intrinsic clearance is independent of
tamsulosin hydrochloride binding to AAG, but diminishes with age, resulting in a
40% overall higher exposure (AUC) in subjects of age 55 to 75 years compared to
subjects of age 20 to 32 years [
see Use in Specific Populations (8.5)].
Renal Impairment
The pharmacokinetics
of tamsulosin hydrochloride have been compared in 6 subjects with mild-moderate
(30 ≤CL
cr <70 mL/min/1.73 m
2)
or moderate-severe (10 ≤CL
cr <30 mL/min/1.73 m
2) renal impairment and 6 normal subjects (CL
cr >90 mL/min/1.73 m
2). While a change in the overall plasma concentration of
tamsulosin hydrochloride was observed as the result of altered binding to AAG,
the unbound (active) concentration of tamsulosin hydrochloride, as well as the
intrinsic clearance, remained relatively constant. Therefore, patients with
renal impairment do not require an adjustment in tamsulosin hydrochloride
capsules dosing. However, patients with endstage renal disease (CL
cr <10 mL/min/1.73 m
2) have not been
studied [
see Use in Specific Populations (8.6)].
Hepatic Impairment
The pharmacokinetics
of tamsulosin hydrochloride have been compared in 8 subjects with moderate
hepatic impairment (Child-Pugh's classification: Grades A and B) and 8 normal
subjects. While a change in the overall plasma concentration of tamsulosin
hydrochloride was observed as the result of altered binding to AAG, the unbound
(active) concentration of tamsulosin hydrochloride does not change
significantly, with only a modest (32%) change in intrinsic clearance of unbound
tamsulosin hydrochloride. Therefore, patients with moderate hepatic impairment
do not require an adjustment in tamsulosin hydrochloride capsules dosage.
Tamsulosin hydrochloride have not been studied in patients with severe hepatic
impairment [
see Use in Specific Populations (8.7)].
Drug Interactions
Cytochrome P450 Inhibition
Strong and Moderate Inhibitors of CYP3A4 or CYP2D6
The
effects of ketoconazole (a strong inhibitor of CYP3A4) at 400 mg once daily for
5 days on the pharmacokinetics of a single tamsulosin hydrochloride capsule 0.4
mg dose was investigated in 24 healthy volunteers (age range 23 to 47 years).
Concomitant treatment with ketoconazole resulted in an increase in the C
max and AUC of tamsulosin by a factor of 2.2 and 2.8,
respectively [
see Warnings and Precautions (5.2) and
Clinical Pharmacology (12.3)]. The effects of concomitant administration
of a moderate CYP3A4 inhibitor (e.g., erythromycin) on the pharmacokinetics of
tamsulosin hydrochloride have not been evaluated [
see Warnings and Precautions (5.2) and Drug Interactions
(7.1)].
The effects of paroxetine (a strong inhibitor of CYP2D6)
at 20 mg once daily for 9 days on the pharmacokinetics of a single tamsulosin
hydrochloride capsule 0.4 mg dose was investigated in 24 healthy volunteers (age
range 23 to 47 years). Concomitant treatment with paroxetine resulted in an
increase in the C
max and AUC of tamsulosin by a factor of
1.3 and 1.6, respectively [
see Warnings and Precautions
(5.2) and Drug Interactions (7.1)]. A similar increase in exposure is
expected in CYP2D6 poor metabolizers (PM) as compared to extensive metabolizers
(EM). A fraction of the population (about 7% of Caucasians and 2% of African
Americans) are CYP2D6 PMs. Since CYP2D6 PMs cannot be readily identified and the
potential for significant increase in tamsulosin exposure exists when tamsulosin
hydrochloride 0.4 mg is coadministered with strong CYP3A4 inhibitors in CYP2D6
PMs, tamsulosin hydrochloride 0.4 mg capsules should not be used in combination
with strong inhibitors of CYP3A4 (e.g., ketoconazole) [
see Warnings and Precautions (5.2) and Drug Interactions
(7.1)].
The effects of concomitant administration of a moderate
CYP2D6 inhibitor (e.g., terbinafine) on the pharmacokinetics of tamsulosin
hydrochloride have not been evaluated [
see Warnings and
Precautions (5.2) and Drug Interactions (7.1)].
The effects of
coadministration of both a CYP3A4 and a CYP2D6 inhibitor with tamsulosin
hydrochloride capsules have not been evaluated. However, there is a potential
for significant increase in tamsulosin exposure when tamsulosin hydrochloride
0.4 mg is coadministered with a combination of both CYP3A4 and CYP2D6
inhibitors [
see Warnings and Precautions (5.2) and Drug
Interactions (7.1)].
Cimetidine
The effects of cimetidine at the highest recommended dose (400 mg
every 6 hours for 6 days) on the pharmacokinetics of a single tamsulosin
hydrochloride capsule 0.4 mg dose was investigated in 10 healthy volunteers (age
range 21 to 38 years). Treatment with cimetidine resulted in a significant
decrease (26%) in the clearance of tamsulosin hydrochloride, which resulted in a
moderate increase in tamsulosin hydrochloride AUC (44%) [
see Warnings and Precautions (5.2) and Drug Interactions
(7.1)].
Other Alpha Adrenergic Blocking
Agents
The pharmacokinetic and pharmacodynamic interactions between
tamsulosin hydrochloride capsules and other alpha adrenergic blocking agents
have not been determined; however, interactions between tamsulosin hydrochloride
capsules and other alpha adrenergic blocking agents may be expected [
see Warnings and Precautions (5.2) and Drug Interactions
(7.2)].
PDE5 Inhibitors
Caution
is advised when alpha adrenergic blocking agents including tamsulosin
hydrochloride are coadministered with PDE5 inhibitors Alpha-adrenergic blockers
and PDE5 inhibitors are both vasodilators that can lower blood pressure.
Concomitant use of these two drug classes can potentially cause symptomatic
hypotension [
see Warnings and Precautions (5.2) and Drug
Interactions (7.3)]
Warfarin
A
definitive drug-drug interaction study between tamsulosin hydrochloride and
warfarin was not conducted. Results from limited
in vitro and
in vivo studies
are inconclusive. Therefore, caution should be exercised with concomitant
administration of warfarin and tamsulosin hydrochloride capsules [
see Warnings and Precautions (5.2) and Drug Interactions
(7.4)].
Nifedipine, Atenolol, Enalapril
In three studies in hypertensive subjects (age range 47 to 79 years)
whose blood pressure was controlled with stable doses of nifedipine, atenolol,
or enalapril for at least 3 months, tamsulosin hydrochloride capsules 0.4 mg for
7 days followed by tamsulosin hydrochloride capsules 0.8 mg for another 7 days
(n=8 per study) resulted in no clinically significant effects on blood pressure
and pulse rate compared to placebo (n=4 per study). Therefore, dosage
adjustments are not necessary when tamsulosin hydrochloride capsules are
administered concomitantly with nifedipine, atenolol, or enalapril [
see Drug Interactions (7.5)].
Digoxin and Theophylline
In two studies in healthy
volunteers (n=10 per study; age range 19 to 39 years) receiving tamsulosin
hydrochloride capsules 0.4 mg/day for 2 days, followed by tamsulosin
hydrochloride capsules 0.8 mg/day for 5 to 8 days, single intravenous doses of
digoxin 0.5 mg or theophylline 5 mg/kg resulted in no change in the
pharmacokinetics of digoxin or theophylline. Therefore, dosage adjustments are
not necessary when a tamsulosin hydrochloride capsule is administered
concomitantly with digoxin or theophylline [
see Drug
Interactions (7.6)].
Furosemide
The pharmacokinetic and pharmacodynamic interaction between
tamsulosin hydrochloride capsules 0.8 mg/day (steady-state) and furosemide 20 mg
intravenously (single dose) was evaluated in ten healthy volunteers (age range
21 to 40 years). Tamsulosin hydrochloride capsules had no effect on the
pharmacodynamics (excretion of electrolytes) of furosemide. While furosemide
produced an 11% to 12% reduction in tamsulosin hydrochloride C
max and AUC, these changes are expected to be clinically
insignificant and do not require adjustment of the tamsulosin hydrochloride
capsules dosage [
see Drug Interactions (7.7)].