Tadalafil 5 mg, Tamsulosin Hcl 0.4 mg (PR) Hard-gelatin capsules

Penile erection during sexual stimulation is caused by increased penile blood flow resulting from the relaxation of penile arteries and corpus cavernosal smooth muscle. This response is mediated by the release of nitric oxide (NO) from nerve terminals and endothelial cells, which stimulates the synthesis of cGMP in smooth muscle cells. Cyclic GMP causes smooth muscle relaxation and increased blood flow into the corpus cavernosum. The inhibition of phosphodiesterase type 5 (PDE5) enhances erectile function by increasing the amount of cGMP. Tadalafil inhibits PDE5. Because sexual stimulation is required to initiate the local release of nitric oxide, the inhibition of PDE5 by tadalafil has no effect in the absence of sexual stimulation.

The effect of PDE5 inhibition on cGMP concentration in the corpus cavernosum and pulmonary arteries is also observed in the smooth muscle of the prostate, the bladder and their vascular supply. The mechanism for reducing BPH symptoms has not been established.

Studies in vitrohave demonstrated that tadalafil is a selective inhibitor of PDE5. PDE5 is found in the smooth muscle of the corpus cavernosum, prostate, and bladder as well as in vascular and visceral smooth muscle, skeletal muscle, urethra, platelets, kidney, lung, cerebellum, heart, liver, testis, seminal vesicle, and pancreas.

Over a dose range of 2.5 to 20 mg, tadalafil exposure (AUC) increases proportionally with dose in healthy subjects. Steady-state plasma concentrations are attained within 5 days of once per day dosing and exposure is approximately 1.6-fold greater than after a single dose. Mean tadalafil concentrations measured after the administration of a single oral dose of 20 mg and single and once daily multiple doses of 5 mg, from a separate study, ( see Figure 4) to healthy male subjects are depicted in Figure 4.

Absorption — After single oral-dose administration, the maximum observed plasma concentration (C max) of tadalafil is achieved between 30 minutes and 6 hours (median time of 2 hours). Absolute bioavailability of Tadalafil following oral dosing has not been determined.

The rate and extent of absorption of tadalafil are not influenced by food; thus tadalafil tablets may be taken with or without food.

Distribution —The mean apparent volume of distribution following oral administration is approximately 63 L, indicating that tadalafil is distributed into tissues. At therapeutic concentrations, 94% of tadalafil in plasma is bound to proteins. Less than 0.0005% of the administered dose appeared in the semen of healthy subjects.

Metabolism — Tadalafil is predominantly metabolized by CYP3A4 to a catechol metabolite. The catechol metabolite undergoes extensive methylation and glucuronidation to form the methylcatechol and methylcatechol glucuronide conjugate, respectively. The major circulating metabolite is the methylcatechol glucuronide. Methylcatechol concentrations are less than 10% of glucuronide concentrations. In vitro data suggests that metabolites are not expected to be pharmacologically active at observed metabolite concentrations.

Excretion —The mean oral clearance for tadalafil is 2.5 L/hr and the mean terminal half-life is 17.5 hours in healthy subjects. Tadalafil is excreted predominantly as metabolites, mainly in the feces (approximately 61% of the dose) and to a lesser extent in the urine (approximately 36% of the dose).

Geriatric — Healthy male elderly subjects (65 years or over) had a lower oral clearance of tadalafil, resulting in 25% higher exposure (AUC) with no effect on C max relative to that observed in healthy subjects 19 to 45 years of age. No dose adjustment is warranted based on age alone. However, greater sensitivity to medications in some older individuals should be considered [see Use in Specific Populations ( 8.5)] .

Patients with Diabetes Mellitus — In male patients with diabetes mellitus after a 10 mg tadalafil dose, exposure (AUC) was reduced approximately 19% and C max was 5% lower than that observed in healthy subjects. No dose adjustment is warranted.

Patients with BPH — In patients with BPH following single and multiple-doses of 20 mg tadalafil, no statistically significant differences in exposure (AUC and C max) were observed between elderly (70 to 85 years) and younger (≤60 years of age) subjects. No dose adjustment is warranted.

The symptoms associated with benign prostatic hyperplasia (BPH) are related to bladder outlet obstruction, which is comprised of two underlying components: static and dynamic. The static component is related to an increase in prostate size caused, in part, by a proliferation of smooth muscle cells in the prostatic stroma. However, the severity of BPH symptoms and the degree of urethral obstruction do not correlate well with the size of the prostate. The dynamic component is a function of an increase in smooth muscle tone in the prostate and bladder neck leading to constriction of the bladder outlet. Smooth muscle tone is mediated by the sympathetic nervous stimulation of alpha1 adrenoceptors, which are abundant in the prostate, prostatic capsule, prostatic urethra, and bladder neck. Blockade of these adrenoceptors can cause smooth muscles in the bladder neck and prostate to relax, resulting in an improvement in urine flow rate and a reduction in symptoms of BPH.

Tamsulosin, an alpha1 adrenoceptor blocking agent, exhibits selectivity for alpha1 receptors in the human prostate. At least three discrete alpha1 adrenoceptor subtypes have been identified: alpha1A, alpha1B, and alpha1D; their distribution differs between human organs and tissue. Approximately 70% of the alpha1 receptors in the human prostate are of the alpha1A subtype.

Tamsulosin hydrochloride capsules are not intended for use as an antihypertensive drug.

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 (Tmax) is reached by 4 to 5 hours under fasting conditions and by 6 to 7 hours when tamsulosin hydrochloride capsules are administered with food. Taking tamsulosin hydrochloride capsules under fasted conditions results in a 30% increase in bioavailability (AUC) and 40% to 70% increase in peak concentrations (Cmax) compared to fed conditions (Figure 1).

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).

Distribution — The mean steady-state apparent volume of distribution of tamsulosin hydrochloride after intravenous administration to 10 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 alpha1 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 4 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 5 to 7 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).

Pediatric Use — Tamsulosin hydrochloride capsules are not indicated for use in pediatric populations [see Use in Specific Populations (8.4)].