Tadalafil: Original Package Insert, Indications, and How to Take?
Results of Efficacy
5mg Tablet
Effects of Tadalafil on Erectile Function
Tadalafil, when administered at doses of 2.5 mg, 5 mg, and 10 mg on a daily basis, was subject to evaluation in three comprehensive clinical trials involving a total of 853 diverse patients. These patients spanned a wide range of ages from 21 to 82 years and included various ethnic backgrounds, all presenting with a spectrum of erectile dysfunction (ED) ranging from mild to severe. In the primary efficacy studies involving the general population, a substantial 76% to 85% of participants noted improvements in their erectile quality after taking Tadalafil daily, in stark contrast to the 29% to 30% noted in the placebo group. Furthermore, across all severity levels of erectile dysfunction, patients reported significant enhancements in their erectile performance while on Tadalafil. The findings showed that 62% to 69% of patients taking Tadalafil at the 5 mg dosage reported successful sexual intercourse attempts, compared to only 34% to 39% within the placebo cohort. Notably, the 5 mg dose of Tadalafil demonstrated a profound enhancement in erectile function lasting over 24 hours between doses, making it a reliable option for daily intake.
Effects of Tadalafil on Signs and Symptoms of Benign Prostatic Hyperplasia (BPH)
The 5 mg daily regimen of Tadalafil was evaluated in two rigorous clinical studies involving 749 patients over the age of 45 (with 40% being 65 years or older) presenting with symptoms indicative of Benign Prostatic Hyperplasia (BPH). Additionally, one clinical trial featured 408 patients who suffered from BPH symptoms coupled with erectile dysfunction. The studies aimed primarily at quantifying improvements in the International Prostate Symptom Score (IPSS) over a 12-week treatment period revealed statistically significant enhancements (p<0.005) in symptoms associated with BPH in patients receiving Tadalafil 5 mg versus the placebo group at the conclusion of this timeframe.
Efficacy in Erectile Dysfunction in Patients with Diabetes Mellitus
Tadalafil's efficacy in addressing erectile dysfunction within diabetic patient populations has been proven through once-daily administration. All seven foundational efficacy studies that included the general population with ED (N=235) also encompassed a specific study focused solely on diabetic patients (both Type 1 and Type 2) exhibiting erectile dysfunction (N=216). A multicenter, double-blind, randomized clinical trial demonstrated statistically significant improvements in erectile function among diabetic individuals treated with daily Tadalafil.
20mg Tablet
Study Design
To evaluate the efficacy and safety of Tadalafil in treating erectile dysfunction, 22 clinical studies lasting up to 24 weeks were conducted, encompassing more than 4,000 patients. The studies examined dosage ranges from 2 mg to 100 mg, taken on an as-needed basis or as a daily regimen. Tadalafil has consistently proven effective in enhancing erectile function in men suffering from erectile dysfunction (ED).
Effects of Tadalafil on Erectile Function
The results across all studies indicated that Tadalafil produced consistent and statistically significant improvements compared to placebo in all primary and secondary efficacy endpoints evaluated. Notably, the efficacy of Tadalafil did not diminish over time. With doses ranging from 2 mg to 100 mg, 16 clinical studies involving 3,250 patients demonstrated that 81% of participants reported improvements in their erectile performance. Patients with ED across varying severity levels also noted enhancements in their responses while using Tadalafil, with 86%, 83%, and 72% satisfaction reported for mild, moderate, and severe ED respectively.
Response Period
In three different clinical studies involving 1,054 patients conducted in at-home settings, the response period to Tadalafil was clearly defined. The results indicated that Tadalafil significantly improved erectile function and the ability to engage in satisfactory sexual intercourse for up to 36 hours post-dose. In addition, patients demonstrated the capacity to achieve and maintain erections conducive to satisfying sexual experiences significantly more than those in the placebo group, starting as early as 30 minutes post-administration.
Patient Confidence and Sexual Satisfaction
The International Index of Erectile Function (IIEF) also evaluates patient confidence in achieving and maintaining adequate erections suitable for sexual intercourse. Tadalafil significantly bolstered patient confidence. Analyses assessing the Sexual Relationship Satisfaction and Global Satisfaction domains of the IIEF further indicated that Tadalafil treatment resulted in notable increases in sexual satisfaction within both areas evaluated. Additionally, Tadalafil contributed to a heightened proportion of sexual encounters deemed satisfactory by both the patient and their partner.
Efficacy in Erectile Dysfunction in Patients with Diabetes Mellitus
In studies involving diabetic patients (N=451), Tadalafil showed efficacy in treating erectile dysfunction. All primary efficacy studies included patients suffering from diabetes, with one specific study focusing exclusively on diabetic individuals (Type 1 or Type 2) experiencing erectile dysfunction. Tadalafil resulted in statistically significant improvements in erectile functionality and sexual satisfaction. In these studies, 68% of patients with diabetes treated with the 20 mg dosage reported enhanced erectile function.
Efficacy in Erectile Dysfunction in Patients Who Underwent Radical Prostatectomy
Tadalafil's efficacy has also been illustrated in patients who developed erectile dysfunction post-bilateral nerve-sparing radical prostatectomy. A randomized, placebo-controlled, double-blind, parallel prospective study involving this patient population (N=303) demonstrated clinically significant improvements in erectile function, with 62% of participants reporting better erection quality after Tadalafil 20 mg administration.
Pharmacological Characteristics
5mg Tablet
Pharmacokinetic Properties
Absorption
Following oral administration, Tadalafil is absorbed swiftly, reaching an average peak plasma concentration (Cmax) within approximately 2 hours. Although the absolute bioavailability of Tadalafil post-oral dosing remains undetermined, its absorption rate and extent are unaffected by food intake, allowing for flexible dosing with or without food. Additionally, the timing of administration (morning versus evening) bears no significant impact on its pharmacokinetics.
Distribution
The calculated average volume of distribution approximates 63 liters, indicating substantial distribution of Tadalafil within bodily tissues. At therapeutic concentrations, about 94% of Tadalafil binds to plasma proteins, and remarkably, less than 0.0005% of the administered dose is detected in the semen of healthy individuals.
Metabolism
Tadalafil is predominantly metabolized by the cytochrome P450 (CYP) isoform 3A4, with the main circulating metabolite being methylcatechol glucuronide. This metabolite exhibits a potency at least 13,000 times lower than Tadalafil for PDE5, thereby rendering it unlikely to demonstrate any clinical efficacy at observed metabolite concentrations.
Elimination
The mean oral clearance rate for Tadalafil is recorded at 2.5 L/h, with an average half-life of 17.5 hours observed in healthy individuals. The drug is primarily excreted as metabolites, predominantly via feces (approximately 61% of the administered dose) and to a lesser extent through urine (approximately 36%).
Pharmacokinetics in Special Populations
Older Adults
Healthy elderly individuals aged 65 years and above demonstrate lower oral clearance levels for Tadalafil, resulting in a 25% increase in exposure (AUC) compared to their younger counterparts aged 19 to 45 years. This age-related variation does not require any adjustments in dosing.
Pediatric Population
Tadalafil's safety and efficacy in individuals under the age of 18 have yet to be thoroughly evaluated.
Hepatic Impairment
The AUC exposure levels for Tadalafil in individuals with mild to moderate hepatic impairment (Child-Pugh Classes A and B) is comparable to those observed in healthy individuals. However, data regarding patients with severe hepatic impairment (Child-Pugh Class C) remains unavailable.
Renal Impairment
Patients with renal impairment, including those on hemodialysis, exhibit increased AUC exposure to Tadalafil compared to healthy individuals.
Diabetic Patients
In diabetic patients, Tadalafil's AUC exposure is approximately 19% lower than that of healthy individuals. However, this exposure variation does not necessitate adjustments in dosing.
Studies of Tadalafil on Heart Rate and Blood Pressure
Research has indicated that Tadalafil administration to healthy individuals does not result in significant changes in systolic and diastolic blood pressure—both in supine (average maximum decrease of 1.6/0.8 mmHg) and standing positions (average maximum decrease of 0.2/4.6 mmHg). Moreover, no significant alterations in heart rate were recorded, apart from individuals concurrently using nitrates, who reported greater effects.
Interaction with Nitrates
A dedicated study was undertaken to evaluate the interaction between nitrates and Tadalafil, with the goal of establishing a safe interval post-Tadalafil administration during which no clinically significant interaction affecting blood pressure occurs. Participants, including those with diabetes and/or controlled hypertension, received 20 mg of Tadalafil or placebo daily for a week, followed by a single dose of 0.4 mg of sublingual nitroglycerin at designated intervals after the last Tadalafil administration. The results suggested no interaction was observable after 48 hours post the last Tadalafil dose.
The concomitant use of Tadalafil with nitrates is strictly contraindicated. If nitrate administration becomes absolutely necessary in patients who have recently taken Tadalafil, a minimum period of 48 hours should be allowed after the last Tadalafil dose before nitrates are given. Such cases require careful medical supervision and adequate monitoring of hemodynamic parameters.
Effects on Semen Characteristics
Analysis revealed no clinically significant effects on semen characteristics following Tadalafil use.
Studies of Tadalafil on Vision
In investigations assessing Tadalafil's impact on vision, participants did not demonstrate difficulties in color discrimination, specifically in blue/green outputs, as assessed by the Farnsworth-Munsell 100 color test. This outcome aligns with Tadalafil's low binding affinity for PDE6 relative to PDE5.
Furthermore, no apparent impacts were documented on visual acuity, electroretinograms, intraocular pressure, or pupillometry. Throughout the clinical studies, reports concerning changes in color vision remained rare (<0.1%).
Studies on Spermatogenesis
Three investigations were conducted focusing on men to assess potential effects of daily doses of 10 mg (one six-month study) and 20 mg (one six-month study and one nine-month study) of Tadalafil on spermatogenesis. No adverse reactions concerning sperm morphology or motility were identified in any of the studies. It was noted that in the six-month study using 10 mg Tadalafil daily and the nine-month study utilizing 20 mg daily, average sperm concentration was diminished compared to placebo, although this effect was not witnessed in the six-month study of 20 mg. During the nine-month assessment, decreased sperm concentration corresponded with an uptick in ejaculation frequency, although this frequency was not measured in the six-month studies. Importantly, no adverse effects were seen regarding mean concentrations of reproductive hormones (testosterone, luteinizing hormone, and follicle-stimulating hormone) across both 10 mg and 20 mg Tadalafil doses in comparison with the placebo group.
20mg Tablet
Description
Tadalafil, an oral medication specifically designed for the treatment of erectile dysfunction, functions as a potent and selective reversible inhibitor of cyclic guanosine monophosphate (cGMP) specific phosphodiesterase type 5 (PDE5). Its empirical formula is C22H19N3O4, correlating with a molecular weight of 389.41. The 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 is characterized as a crystalline solid that is largely insoluble in water and exhibits minimal solubility in ethanol.
Pharmacodynamic Properties
Upon sexual stimulation, leading to localized nitric oxide release, Tadalafil's inhibition of PDE5 elevates levels of cGMP within the corpus cavernosum. This mechanism results in the relaxation of smooth muscle and enhances blood circulation to the penile tissue, facilitating an erection. Importantly, Tadalafil does not exert any effect in the absence of sexual arousal.
In vitro evaluations demonstrate that Tadalafil effectively inhibits PDE5, which is predominantly located within the smooth muscle of the corpus cavernosum, prostate, and bladder, as well as in vascular and visceral smooth muscle, skeletal muscle, platelets, kidneys, lungs, cerebellum, and pancreas. The inhibition potency of Tadalafil for PDE5 significantly exceeds that for the other phosphodiesterases, being more than 10,000 times more potent against PDE5 relative to PDE1, PDE2, PDE4, and PDE7, enzymes found in cardiac, cerebral, vascular, hepatic, leukocyte, and skeletal systems. Additionally, Tadalafil shows more than 10,000 times greater efficacy against PDE5 when contrasted with PDE3, an enzyme relevant to cardiac contractility, and approximately 700 times more potent against PDE5 than PDE6, which is involved in visual phototransduction. Tadalafil also surpasses the potency of PDE5 over PDE8, 9, and 10 by 9,000 times, and is 14 times more potent for PDE5 than for PDE11, although the precise tissue distribution and physiological effects resulting from the inhibition of PDE8 to PDE11 are yet to be established.
Pharmacokinetic Properties
Absorption
Following oral intake, Tadalafil is rapidly absorbed, achieving average peak plasma concentration (Cmax) within around 2 hours. The absolute bioavailability of Tadalafil following oral administration has not been definitively determined. Notably, the extent and rate of Tadalafil absorption remain unaffected by food, permitting concurrent intake with meals. Furthermore, there is no clinically significant difference in absorption based on whether the medication is taken in the morning or evening.
Distribution
The average volume of distribution is estimated at around 63 liters, evidencing that Tadalafil is extensively distributed in body tissues. Therapeutically, 94% of Tadalafil binds to plasma proteins, with less than 0.0005% of the given dose appearing within the semen of healthy volunteers.
Metabolism
Tadalafil undergoes substantial metabolism primarily through the cytochrome P450 (CYP) isoform 3A4. The principal circulating metabolite is methylcatechol glucuronide, which has a potency that is at least 13,000 times less effective than Tadalafil for PDE5, thus rendering it unlikely to display clinically relevant activity at recognized metabolite concentrations.
Elimination
The mean oral clearance rate for Tadalafil is reported at 2.5 L/h and an estimated average half-life of about 17.5 hours in healthy subjects. Metabolites primarily excrete Tadalafil, with an approximate 61% of the dose eliminated via feces and about 36% through urine.
Pharmacokinetics in Special Populations
Older Adults
Within the demographic of healthy elderly individuals (aged 65 and above), a pronounced reduction in oral clearance of Tadalafil is noted, correlating with 25% heightened exposure (AUC) compared to younger healthy individuals aged 19 to 45 years. This age-related effect does not demand any adjustments in the recommended dosage.
Pediatric Population
The safety and efficacy profiles of Tadalafil in individuals below the age of 18 have not undergone extensive evaluation.
Hepatic Impairment
Tadalafil's AUC levels in individuals exhibiting mild to moderate hepatic impairment (Child-Pugh Classes A and B) show comparable results to those found in healthy subjects. However, comprehensive data on patients with severe hepatic impairment (Child-Pugh Class C) are lacking.
Renal Impairment
In subjects with renal impairment, including those undergoing hemodialysis, the AUC associated with Tadalafil is elevated in comparison to healthy individuals.
Diabetic Patients
The AUC for Tadalafil in diabetic individuals is roughly 19% lower than those of healthy subjects, although this difference does not necessitate any dosage adjustments.
Studies of Tadalafil on Heart Rate and Blood Pressure
Tadalafil administration in healthy subjects did not produce significant deviations compared to the placebo group in measuring systolic and diastolic blood pressure while supine (average maximum decrease of 1.6/0.8 mmHg) and standing (average maximum decrease of 0.2/4.6 mmHg), nor was there any notable variation in heart rate. Enhanced effects were noted in patients also utilizing nitrates concurrently.
Interaction with Nitrates
An investigation focused on understanding the interaction dynamic between nitrates and Tadalafil was carried out, with the aim of establishing a safe window post-Tadalafil that avoids clinically significant interactions impacting blood pressure. Participants, which included diabetic and hypertensive patients with well-regulated blood pressure, received either daily doses of 20 mg Tadalafil or placebo over a week, thereafter receiving a single dose of 0.4 mg of sublingual nitroglycerin at pre-defined intervals following the last Tadalafil intake. The conclusion was that no clinically significant interaction arose within a 48-hour window after the last Tadalafil administration.
It is imperative to note that concurrent administration of Tadalafil with nitrates is contraindicated. In scenarios where the administration of nitrates must be pursued after Tadalafil intake, it is crucial to observe a minimum gap of 48 hours from the last dose of Tadalafil prior to nitrate use. This should be handled under stringent medical supervision with continuous monitoring of hemodynamic responses.
Effects on Semen Characteristics
Clinical assessments indicated no meaningful effects on semen parameters following Tadalafil administration.
Studies of Tadalafil on Vision
Investigations involving Tadalafil's influence on visual functions revealed no discernible issues with color discrimination (specifically blue/green) per the Farnsworth-Munsell 100 color test. This finding is consistent with Tadalafil’s low binding affinity for PDE6, relative to PDE5.
Additionally, no significant modifications were noted concerning visual acuity, electroretinogram readings, intraocular pressure, or pupillary response metrics. Across a multitude of clinical studies, reports of modifications in color vision were infrequent (<0.1%).
Studies on Spermatogenesis
Three clinical studies were methodically executed to assess the potential ramifications of Tadalafil doses of 10 mg (one six-month study) and 20 mg (one six-month study and one nine-month study) on spermatogenesis among male participants. Findings illustrated no adverse impacts on sperm morphology or motility across any studies. However, a decrease in average sperm concentration was observed in the six-month trial utilizing 10 mg and the nine-month trial with 20 mg compared to placebo, although this wasn’t observed in the six-month 20 mg study. The decrease in sperm concentration during the nine-month evaluation correlated with an increase in ejaculation frequency, the latter of which was not assessed in the six-month studies. No adverse alterations were reported concerning mean reproductive hormone concentrations (testosterone, luteinizing hormone, or follicle-stimulating hormone) for either the 10 mg or 20 mg Tadalafil doses as compared to the placebo group.