Tadalafil: Original Label, Indications and How to Take 5mg?

Effectiveness Results

5mg Tablet

Effects of Tadalafil on Erectile Function

Tadalafil, when administered at doses of 2.5 mg, 5 mg, and 10 mg daily, was evaluated in three significant clinical studies involving a diverse group of 853 patients, aged between 21 and 82 years. These studies encompassed various ethnic backgrounds and degrees of severity of erectile dysfunction, classified as mild, moderate, or severe. In two pivotal efficacy studies involving the general population, remarkable results were reported: 76% and 85% of patients indicated that the daily use of tadalafil substantially improved their erections, compared to only 29% and 30% of those receiving a placebo. Furthermore, the efficacy of tadalafil was consistent across all levels of erectile dysfunction severity, with 62% and 69% of participants successfully achieving sexual intercourse after using the 5 mg dose, as opposed to 34% and 39% in the placebo group. Notably, the 5 mg dosage of tadalafil maintains the enhancement of erectile function for over 24 hours.

Effects of Tadalafil on Symptoms of Benign Prostatic Hyperplasia

The 5 mg dose of tadalafil was also analyzed in two clinical studies, which included 749 patients older than 45 years, with 40% of this group exceeding 65 years of age, who were diagnosed with symptoms of Benign Prostatic Hyperplasia (BPH). An additional study examined 408 patients suffering from both BPH symptoms and erectile dysfunction. The primary goal over 12 weeks of treatment was to improve the International Prostate Symptom Score (IPSS). Statistically significant improvements (p<0.005) were observed in patients receiving tadalafil compared to those on placebo in terms of alleviating BPH symptoms at the conclusion of the trial.

Efficacy in Erectile Dysfunction among Patients with Diabetes Mellitus

In diabetic patients, tadalafil administered once daily demonstrated effective treatment for erectile dysfunction. All seven primary efficacy studies investigating the general population with erectile dysfunction (N=235) incorporated diabetic patients, and one dedicated study involving 216 patients with either Type 1 or Type 2 diabetes confirmed tadalafil's consistent statistical significance in enhancing erectile function.

20mg Tablet

Study Design

The safety and efficacy of tadalafil for erectile dysfunction were assessed across 22 clinical studies lasting up to 24 weeks, involving over 4,000 patients, with doses ranging from 2 mg to 100 mg taken as needed, up to once daily. The results confirmed tadalafil's effectiveness in improving erectile function among men suffering from erectile dysfunction (ED).

To analyze tadalafil’s efficacy, several assessment tools were utilized. Global Assessment Questions (GAQ) were employed to measure treatment effectiveness in enhancing patient erections. During these studies, both patients and their partners logged their experiences in Sexual Encounter Profile (SEP) diaries, detailing erectile function and satisfaction from each sexual attempt. The International Index of Erectile Function (IIEF) was also administered to ascertain global measures of erectile function and sexual satisfaction, along with the severity of ED.

Effects of Tadalafil on Erectile Function

Across the studies, tadalafil consistently showed statistically significant benefits compared to placebo in all primary and secondary objectives assessed, with no diminishment of treatment effect over time. Various doses ranging from 2 to 100 mg were evaluated in 16 clinical studies, involving 3,250 patients, representing a broad range of erectile dysfunction severity (mild, moderate, severe), diverse etiologies (including diabetic patients), along with a wide age spectrum (21 to 86 years). In the primary efficacy assessments among the general population, 81% of participants asserted that tadalafil improved their erectile function. Furthermore, improvements were noted across all severity categories of ED: 86% for mild, 83% for moderate, and 72% for severe cases.

Tadalafil demonstrated a significant increase in the patients' ability to achieve an erection adequate for sexual intercourse and to sustain it long enough for satisfactory intercourse, as measured by SEP diaries. In the primary efficacy studies, it was determined that 75% of sexual attempts were successful for those treated with tadalafil.

Moreover, tadalafil showed statistically significant advancement in erectile function as measured by the Erectile Function Domain of the IIEF. In primary efficacy assessments, approximately 60% of patients on the 20 mg dosage of tadalafil achieved normal erectile function during treatment.

Response Period

Three clinical trials involving 1,054 patients in a domestic setting were performed to ascertain the response period following tadalafil administration. Results indicated a statistically significant enhancement in erectile function and the ability to engage in satisfactory sexual activities for up to 36 hours after dosing. Patients demonstrated improved capacity for both initiating and sustaining erections sufficient for sexual intercourse, beginning as early as 30 minutes post-ingestion, when compared to placebo counterparts.

Patient Confidence and Sexual Satisfaction

The IIEF assessment included measures of patient confidence in achieving and maintaining adequate erection for sexual activities. Treatment with tadalafil significantly bolstered patient confidence. Analysis of the Sexual Satisfaction and Global Satisfaction domains of the IIEF unveiled statistically significant increases in overall sexual satisfaction as reported by both domains. Additionally, there was a notable improvement in the percentage of sexual encounters that were deemed satisfactory for both patients and their partners.

Efficacy in Erectile Dysfunction among Patients Who Underwent Radical Prostatectomy

Tadalafil has proven effective for individuals who experienced erectile dysfunction post-radical prostatectomy with bilateral nerve sparing. In a randomized, placebo-controlled, double-blind, parallel, and prospective study including this demographic (N=303), tadalafil indicated clinically significant improvements in erectile function, with 62% of participants noting enhanced erections while using 20 mg of tadalafil.

Pharmacological Characteristics

5mg Tablet

Pharmacokinetic Properties

Absorption

Tadalafil is rapidly absorbed following oral administration, with an average time to achieve the maximum plasma concentration (C_max) within approximately 2 hours post-administration. The absolute bioavailability of tadalafil post-oral dosing remains undetermined. Notably, the rate and extent of tadalafil absorption are unaffected by food intake, permitting administration with or without meals. The timing of intake (morning versus evening) does not exhibit clinically significant effects on absorption rates or extents.

Distribution

The average distribution volume is around 63 liters, indicating substantial tissue distribution of tadalafil. At therapeutic doses, approximately 94% of tadalafil is bound to plasma proteins. Notably, less than 0.0005% of the administered dose can be detected in the semen of healthy individuals.

Metabolism

Tadalafil is primarily metabolized by cytochrome P450 (CYP) isoform 3A4, forming a major circulating metabolite known as methylcatechol glucuronide, which possesses a potency less than 13,000 times that of tadalafil against PDE5. Therefore, it is anticipated to be non-active at metabolite concentrations observed.

Elimination

The average oral clearance rate for tadalafil is noted to be 2.5 L/h, with an average half-life of 17.5 hours in healthy subjects. The majority of tadalafil is excreted as metabolites, predominantly through feces (approximately 61% of the oral dose) and a smaller fraction through urine (approximately 36% of the dose).

In a dosing range from 2.5 mg to 20 mg, exposure (area under the curve - AUC) is shown to increase proportionally with the administered dose in healthy individuals. Steady-state plasma concentrations are achieved within 5 days of daily dosing. The pharmacokinetics observed in erectile dysfunction patients are comparable to those in non-erectile dysfunction individuals.

Pharmacokinetics in Special Populations

Geriatric Population

In healthy elderly individuals (aged 65 years or older), the oral clearance of tadalafil was found to be lower, causing an approximately 25% increase in AUC exposure compared to younger healthy subjects (19 to 45 years). This age-related difference is not clinically significant, warranting no dosage adjustment.

Pediatric Population

Research is lacking regarding the application of tadalafil in individuals under 18 years.

Hepatic Insufficiency

In cases of mild to moderate hepatic insufficiency (Child-Pugh Classes A and B), tadalafil exposure (AUC) is comparable to that in healthy populations, whereas data for severe hepatic insufficiency (Child-Pugh Class C) remains unavailable.

Renal Insufficiency

For patients with renal insufficiency, including those undergoing hemodialysis, tadalafil exposure (AUC) was observed to be higher than that found in healthy individuals.

Patients with Diabetes

Exposure to tadalafil (AUC) in diabetic patients averages about 19% less than observed in healthy individuals, which does not necessitate dosage adjustments.

Studies of Tadalafil's Effects on Heart Rate and Blood Pressure

Tadalafil administration in healthy individuals demonstrated negligible differences when compared to the placebo group for systolic and diastolic blood pressures while lying down (average maximum variations of 1.6/0.8 mmHg) and while standing (average maximum variations of 0.2/4.6 mmHg), with no significant changes noted in heart rate. Increased effects were, however, observed in subjects receiving concomitant nitrates.

Interaction with Nitrates

A clinical study was undertaken to evaluate interactions between nitrates and tadalafil. The objective was to establish when, after taking tadalafil, no significant interaction on blood pressure would be present. Participants, which included diabetic and/or hypertensive patients with controlled blood pressure, received either a daily dose of 20 mg tadalafil or placebo for a week, followed by a single 0.4 mg dose of sublingual nitroglycerin at specified intervals post-latest tadalafil intake. The outcomes indicated no interactions following 48 hours after the last dose of tadalafil.

The concurrent usage of tadalafil with nitrates is contraindicated. When absolutely necessary to administer nitrates in patients who have taken tadalafil, a minimum interval of 48 hours after tadalafil administration should be strictly observed. Such circumstances should involve close medical supervision with appropriate monitoring of hemodynamic responses.

Effects on Sperm Characteristics

Clinical evaluations revealed no notable effects on sperm parameters.

Studies of Tadalafil on Vision

An investigation aimed at assessing the impact of tadalafil on visual capabilities indicated no abnormalities in color discrimination (specifically blue/green) per the Farnsworth-Munsell 100 color test results. This aligns with tadalafil's low affinity for PDE6 as opposed to PDE5.

Furthermore, no adverse effects were reported regarding visual acuity, electroretinograms, intraocular pressure, or pupil reactions. Across extensive clinical investigations, incidents of color vision alterations were rare, accounting for less than 0.1% of cases.

Studies on Spermatogenesis

Three separate studies evaluated the potential effects of daily administration of 10 mg (one 6-month study) and 20 mg (one 6-month study and one 9-month study) on spermatogenesis. No adverse results were found in sperm morphology or motility in any conducted studies. In the 6-month investigation with 10 mg and the 9-month study with 20 mg, a decrease in average sperm concentration compared to placebo was documented, albeit without clinical significance. This observation was absent in the 6-month assessment of 20 mg tadalafil. For the 9-month study, the noted decline in sperm concentration correlated with an increased frequency of ejaculation, which was not assessed in the shorter studies. Additionally, no adverse events concerning reproductive hormone concentrations (testosterone, luteinizing hormone, or follicle-stimulating hormone) emerged from either 10 mg or 20 mg tadalafil treatment compared to the placebo group.

20mg Tablet

Description

Tadalafil is an oral therapy for erectile dysfunction and serves as a potent and selective reversible inhibitor of cyclic guanosine monophosphate (cGMP) - specific phosphodiesterase type 5 (PDE5). The empirical formula for tadalafil is C22H19N3O4, reflecting a molecular weight of 389.41. Its chemical nomenclature is pyrazino[1′,2′:1,6]pyrido[3,4-b]indol-1,4-dione,6-(1,3-benzodioxol-5-yl)-2,3,6,7,12,12a-hexahydro-2-methyl-, (6R,12aR). Tadalafil appears as a crystalline solid, predominantly insoluble in water and minimally soluble in ethanol.

Pharmacodynamic Properties

Upon sexual stimulation prompting the localized release of nitric oxide, tadalafil inhibits PDE5, which leads to elevated levels of cGMP in the corpus cavernosum. This biochemical action results in the relaxation of smooth muscle and subsequent increased blood flow into the penile tissues, culminating in an erection. Tadalafil necessitates sexual stimulation for an effect to be observed.

In vitro studies have confirmed that tadalafil is a selective inhibitor of PDE5, which is located within smooth muscle in the corpus cavernosum, prostate, and bladder, as well as in vascular, visceral, skeletal muscle, platelets, kidneys, lungs, cerebellum, and pancreas. Tadalafil exhibits a higher potency against PDE5 compared to other phosphodiesterases. Its potency is over 10,000 times greater for PDE5 than for PDE1, PDE2, PDE4, and PDE7—enzymes present in the heart, brain, blood vessels, liver, leukocytes, and various organ tissues. Furthermore, tadalafil is over 10,000 times more potent against PDE5 than it is against PDE3, which is involved in cardiac contractility. Notably, tadalafil is approximately 700 times more potent in inhibiting PDE5 compared to PDE6, an enzyme implicated in retinal phototransduction. Additionally, it demonstrates a potency greater than 9,000 times in inhibiting PDE5 compared to PDE8, 9, and 10; and 14 times more potency against PDE5 than against PDE11. The specific physiological effects and tissue distribution resulting from inhibition of PDE8 to PDE11 remain to be fully elucidated.

Pharmacokinetic Properties

Absorption

After oral administration, tadalafil is rapidly absorbed, reaching an average C_max approximately within 2 hours. Its absolute bioavailability following oral administration remains unidentified. The rate of absorption is not significantly influenced by food, allowing for flexible administration with or without meals. Timing of ingestion (morning vs. evening) does not yield clinically relevant effects on the absorption dynamics.

Distribution

Tadalafil possesses an average distribution volume of around 63 liters, indicating extensive tissue distribution. At therapeutic concentrations, 94% of tadalafil binds to plasma proteins. Additionally, less than 0.0005% of the administered dose can be found in the semen of healthy subjects.

Metabolism

Majority of tadalafil is metabolized by CYP3A4. The principal circulating metabolite, methylcatechol glucuronide, possesses at least 13,000 times lesser potency for PDE5 and is not expected to exhibit clinical activity at observed metabolite concentrations.

Elimination

The average clearance rate for tadalafil is documented at 2.5 L/h, with a half-life averaging 17.5 hours in healthy individuals. Primarily, tadalafil is excreted as metabolites, mainly via feces (approximately 61% of total dose) and a lesser portion through urine (approximately 36%).

The pharmacokinetic parameters of tadalafil display linear relationships concerning time and dose. In the range of 2.5 mg to 20 mg, the area under the curve (AUC) shows a proportional increase with dosage. Steady-state plasma concentrations are attained within 5 days of continuous daily administration. The pharmacokinetics observed in patients with erectile dysfunction is similar to that in healthy individuals.

Pharmacokinetics in Special Populations

Geriatric Population

Healthy elderly individuals (aged 65 and older) have shown lower tadalafil clearance, resulting in a 25% increase in AUC exposure versus younger healthy subjects (19 to 45 years). This difference in age is not clinically significant, exempting the need for dosage adjustment.

Pediatric Population

There is no evaluation of tadalafil for individuals under the age of 18.

Hepatic Insufficiency

In individuals with mild to moderate liver impairment (Child-Pugh Classes A and B), tadalafil exposure (AUC) appears to be comparable to that of healthy individuals. No data are available for patients with severe hepatic insufficiency (Child-Pugh Class C).

Renal Insufficiency

In patients with renal insufficiency, including those on hemodialysis, tadalafil AUC was noted to be higher than in healthy individuals.

Patients with Diabetes

Patients with diabetes present an AUC for tadalafil that is approximately 19% lower than that of healthy individuals, and this variation does not necessitate a dose adjustment.

Studies on Tadalafil’s Effects on Heart Rate and Blood Pressure