CIALIS Tadalafil 5mg - 1 Tab
RXDRUG-DR-XY43863-1pc
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RXDRUG-DR-XY44985-1pc-laz2
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RXDRUG-DR-XY44985-1pc
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₱95700 | |||
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₱7,42000 | |||
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In stock
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₱26500 |
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Features
Brand
CIALIS
Full Details
Dosage Strength
5 mg
Drug Ingredients
- Tadalafil
Drug Packaging
Film-Coated Tablet 1's
Generic Name
Tadalafil
Dosage Form
Film-Coated Tablet
Registration Number
DR-XY43863
Drug Classification
Prescription Drug (RX)
Description
Indications/Uses
Treatment of erectile dysfunction in adult males.
In order for tadalafil to be effective, sexual stimulation is required.
In order for tadalafil to be effective, sexual stimulation is required.
Dosage/Direction for Use
For oral use.
Use in adult men: The recommended dose of tadalafil is 20 mg taken prior to anticipated sexual activity and without regard to food. It can be taken up to 36 hours and as early as 30 minutes prior to sexual activity. Patients may initiate sexual activity at varying time points relative to dosing in order to determine their own optimal window of responsiveness.
The maximum recommended dosing frequency is once per day.
Use in elderly men: Dosage adjustments are not required in elderly patients.
Use in men with impaired renal function: Dosage adjustments are not required in patients with renal impairment.
Use in men with impaired hepatic function: Dosage adjustments are not required in patients with hepatic impairment (see Precautions).
Use in men with diabetes: Dosage adjustments are not required in diabetic patients.
Use in children: Tadalafil should not be used in individuals below 18 years of age.
Use in adult men: The recommended dose of tadalafil is 20 mg taken prior to anticipated sexual activity and without regard to food. It can be taken up to 36 hours and as early as 30 minutes prior to sexual activity. Patients may initiate sexual activity at varying time points relative to dosing in order to determine their own optimal window of responsiveness.
The maximum recommended dosing frequency is once per day.
Use in elderly men: Dosage adjustments are not required in elderly patients.
Use in men with impaired renal function: Dosage adjustments are not required in patients with renal impairment.
Use in men with impaired hepatic function: Dosage adjustments are not required in patients with hepatic impairment (see Precautions).
Use in men with diabetes: Dosage adjustments are not required in diabetic patients.
Use in children: Tadalafil should not be used in individuals below 18 years of age.
Overdosage
Single doses of up to 500 mg have been given to healthy subjects, and multiple daily doses up to 100 mg have been given to patients. Adverse events were similar to those seen at lower doses. In cases of overdose, standard supportive measures should be adopted as required. Hemodialysis contributes negligibly to tadalafil elimination.
Administration
May be taken with or without food.
Contraindications
In clinical studies, tadalafil was shown to augment the hypotensive effects of nitrates. This is thought to result from the combined effects of nitrates and tadalafil on the nitric oxide/cGMP pathway. Therefore, administration of tadalafil to patients who are using any form of organic nitrate is contraindicated.
Tadalafil should not be used in patients with a known hypersensitivity to tadalafil or to any of the excipients.
Tadalafil should not be used in patients with a known hypersensitivity to tadalafil or to any of the excipients.
Special Precautions
Sexual activity carries a potential cardiac risk for patients with pre-existing cardiovascular disease. Therefore, treatments for erectile dysfunction, including tadalafil should not be used in men with cardiac disease for whom sexual activity is inadvisable. Physicians should consider the potential cardiac risk of sexual activity in patients with pre-existing cardiovascular disease. The following groups of patients with cardiovascular disease were not included in clinical trials: patients with myocardial infarction within the last 90 days; patients with unstable angina or angina occurring during sexual intercourse; patients with New York Heart Association Class 2 or greater heart failure in the last 6 months; patients with uncontrolled arrhythmias, hypotension (<90/50 mm Hg), or uncontrolled hypertension; patients with a stroke within the last 6 months.
Priapism has been reported with PDE5 inhibitors, including tadalafil. Patients who experience erections lasting 4 hours or more should be instructed to seek immediate medical assistance. If priapism is not treated immediately, penile tissue damage and permanent loss of potency may result.
Tadalafil should be used with caution in patients who have conditions that might predispose them to priapism (such as sickle cell anaemia, multiple myeloma, or leukaemia), or in patients with anatomical deformation of the penis (such as angulation, cavernosal fibrosis or Peyronie's disease).
The evaluation of erectile dysfunction should include a determination of potential underlying causes and the identification of appropriate treatment following an appropriate medical assessment.
The safety and efficacy of combinations of tadalafil and other treatments for erectile dysfunction have not been studied. Therefore, the use of such combinations is not recommended.
No data are available in patients with severe hepatic impairment (Child-Pugh Class C), therefore, caution should be exercised when prescribing tadalafil to this patient group.
Caution should be exercised when prescribing tadalafil to patients who are taking alpha [1] blockers such as doxazosin, as simultaneous administration may lead to symptomatic hypotension in some patients. (See Interactions.)
As with other PDE5 inhibitors, tadalafil has systemic vasodilatory properties that may result in transient decreases in blood pressure. Prior to prescribing tadalafil, physicians should carefully consider whether their patients with underlying cardiovascular disease could be affected adversely by such vasodilatory effects.
Nonarteritic anterior ischemic optic neuropathy (NAION) is a cause of decreased vision including permanent loss of vision. There are rare post-marketing reports of NAION in temporal association with the use of all PDE5 inhibitors. Currently it is not possible to determine whether NAION is related directly to the use of PDE5 inhibitors or other factors. Physicians should advise patients to stop use of tadalafil and seek medical attention in the event of a sudden loss of vision. Physicians should also discuss with patients that individuals who have already experienced NAION are at increased risk of NAION.
Effects on ability to drive and use machines: Although the frequency of reports of dizziness in placebo and tadalafil arms in clinical trials was similar, patients should be aware of how they react to tadalafil, before driving or operating machinery.
Priapism has been reported with PDE5 inhibitors, including tadalafil. Patients who experience erections lasting 4 hours or more should be instructed to seek immediate medical assistance. If priapism is not treated immediately, penile tissue damage and permanent loss of potency may result.
Tadalafil should be used with caution in patients who have conditions that might predispose them to priapism (such as sickle cell anaemia, multiple myeloma, or leukaemia), or in patients with anatomical deformation of the penis (such as angulation, cavernosal fibrosis or Peyronie's disease).
The evaluation of erectile dysfunction should include a determination of potential underlying causes and the identification of appropriate treatment following an appropriate medical assessment.
The safety and efficacy of combinations of tadalafil and other treatments for erectile dysfunction have not been studied. Therefore, the use of such combinations is not recommended.
No data are available in patients with severe hepatic impairment (Child-Pugh Class C), therefore, caution should be exercised when prescribing tadalafil to this patient group.
Caution should be exercised when prescribing tadalafil to patients who are taking alpha [1] blockers such as doxazosin, as simultaneous administration may lead to symptomatic hypotension in some patients. (See Interactions.)
As with other PDE5 inhibitors, tadalafil has systemic vasodilatory properties that may result in transient decreases in blood pressure. Prior to prescribing tadalafil, physicians should carefully consider whether their patients with underlying cardiovascular disease could be affected adversely by such vasodilatory effects.
Nonarteritic anterior ischemic optic neuropathy (NAION) is a cause of decreased vision including permanent loss of vision. There are rare post-marketing reports of NAION in temporal association with the use of all PDE5 inhibitors. Currently it is not possible to determine whether NAION is related directly to the use of PDE5 inhibitors or other factors. Physicians should advise patients to stop use of tadalafil and seek medical attention in the event of a sudden loss of vision. Physicians should also discuss with patients that individuals who have already experienced NAION are at increased risk of NAION.
Effects on ability to drive and use machines: Although the frequency of reports of dizziness in placebo and tadalafil arms in clinical trials was similar, patients should be aware of how they react to tadalafil, before driving or operating machinery.
Use In Pregnancy & Lactation
Tadalafil is not indicated for use in women.
There was no evidence of teratogenicity, embryotoxicity or foetotoxicity in rats or mice that received up to 1000 mg/kg/day. In a rat pre- and postnatal development study, the no observed effect dose was 30 mg/kg/day. In the pregnant rat the AUC for calculated free drug at this dose was approximately 18 times the human AUC at a 20 mg dose. There are no studies of tadalafil in pregnant women.
There was no evidence of teratogenicity, embryotoxicity or foetotoxicity in rats or mice that received up to 1000 mg/kg/day. In a rat pre- and postnatal development study, the no observed effect dose was 30 mg/kg/day. In the pregnant rat the AUC for calculated free drug at this dose was approximately 18 times the human AUC at a 20 mg dose. There are no studies of tadalafil in pregnant women.
Adverse Reactions
The most commonly reported adverse events are headache and dyspepsia occurring in approximately 11 and 7% of patients respectively. The adverse events reported with tadalafil were generally mild or moderate, transient, and decreased with continued dosing.
Other common adverse events are back pain, myalgia, nasal congestion, and flushing.
Swelling of eyelids, sensations described as eye pain, conjunctival hyperaemia, dyspnoea and dizziness are uncommon adverse events.
In postmarketing surveillance adverse events that have been reported very rarely in temporal association in patients taking tadalafil include: Body as a whole: hypersensitivity reactions including rash, urticaria, and facial edema, Stevens-Johnson syndrome, and exfoliative dermatitis.
Cardiovascular and cerebrovascular: Serious cardiovascular events, including myocardial infarction, sudden cardiac death, stroke, chest pain, palpitations, and tachycardia, have been reported post marketing in temporal association with the use of tadalafil. Most of the patients in whom these events have been reported had pre-existing cardiovascular risk factors. However, it is not possible to definitively determine whether these events are related directly to these risk factors, to tadalafil, to sexual activity, or to a combination of these or other factors.
Hypotension (more commonly reported when tadalafil is given to patients who are already taking antihypertensive agents), hypertension, and syncope.
Gastrointestinal: abdominal pain and gastroesophageal reflux.
Skin and subcutaneous tissues: hyperhidrosis (sweating).
Urogenital: priapism and prolonged erection.
Special Senses: blurred vision, nonarteritic anterior ischemic optic neuropathy, retinal vein occlusion, visual field defect.
Nervous System: migraine.
Respiratory System: epistaxis.
Other common adverse events are back pain, myalgia, nasal congestion, and flushing.
Swelling of eyelids, sensations described as eye pain, conjunctival hyperaemia, dyspnoea and dizziness are uncommon adverse events.
In postmarketing surveillance adverse events that have been reported very rarely in temporal association in patients taking tadalafil include: Body as a whole: hypersensitivity reactions including rash, urticaria, and facial edema, Stevens-Johnson syndrome, and exfoliative dermatitis.
Cardiovascular and cerebrovascular: Serious cardiovascular events, including myocardial infarction, sudden cardiac death, stroke, chest pain, palpitations, and tachycardia, have been reported post marketing in temporal association with the use of tadalafil. Most of the patients in whom these events have been reported had pre-existing cardiovascular risk factors. However, it is not possible to definitively determine whether these events are related directly to these risk factors, to tadalafil, to sexual activity, or to a combination of these or other factors.
Hypotension (more commonly reported when tadalafil is given to patients who are already taking antihypertensive agents), hypertension, and syncope.
Gastrointestinal: abdominal pain and gastroesophageal reflux.
Skin and subcutaneous tissues: hyperhidrosis (sweating).
Urogenital: priapism and prolonged erection.
Special Senses: blurred vision, nonarteritic anterior ischemic optic neuropathy, retinal vein occlusion, visual field defect.
Nervous System: migraine.
Respiratory System: epistaxis.
Drug Interactions
Effects of other medicinal products on tadalafil: Tadalafil is principally metabolised by CYP3A4. A selective inhibitor of CYP3A4, ketoconazole (400 mg daily), increased tadalafil single-dose exposure (AUC) by 312% and Cmax by 22%, and ketoconazole (200 mg daily), increased tadalafil single-dose exposure (AUC) by 107% and Cmax by 15% relative to the AUC and Cmax values for tadalafil alone.
Ritonavir (200 mg twice daily), an inhibitor of CYP3A4, 2C9, 2C19, and 2D6, increased tadalafil single-dose exposure (AUC) by 124% with no change in Cmax. Although specific interactions have not been studied, other HIV protease inhibitors, such as saquinavir, and other CYP3A4 inhibitors, such as erythromycin and itraconazole, would likely increase tadalafil exposure.
A selective CYP3A4 inducer, rifampicin (600 daily), reduced tadalafil single-dose exposure (AUC) by 88% and Cmax by 46%, relative to the AUC and Cmax values for tadalafil alone. It can be expected that concomitant administration or other CYP3A4 inducers will also decrease plasma concentrations of tadalafil.
Simultaneous administration of an antacid (magnesium hydroxide/aluminum hydroxide) and tadalafil reduced the apparent rate of absorption of tadalafil without altering exposure (AUC) to tadalafil.
An increase in gastric pH resulting from administration of nizatidine, an H2 antagonist had no significant effect on tadalafil pharmacokinetics.
Effects of tadalafil on other medicinal products: In clinical studies, tadalafil was shown to augment the hypotensive effects of nitrates. Therefore, administration of tadalafil to patients who are using any form of organic nitrate is contraindicated (see Contraindications).
Tadalafil is not expected to cause clinically significant inhibition or induction of the clearance of drugs metabolised by CYP450 isoforms. Studies have confirmed that tadalafil does not inhibit or induce CYP450 isoforms, including CYP3A4, CYP1A2, CYP2D6, CYP2E1, CYP2C19, and CYP2C9.
Tadalafil had no clinically significant effect on exposure (AUC) to S-warfarin or R-warfarin (CYP2C9 substrate), nor did tadalafil affect changes in prothrombin time induced by warfarin.
Tadalafil did not potentiate the increase in bleeding time caused by acetyl salicylic acid.
Antihypertensive medications: Tadalafil has systemic vasodilatory properties and may augment the blood pressure lowering effects of antihypertensive agents. Additionally, in patients taking multiple antihypertensive agents whose hypertension was not well controlled, greater reductions in blood pressure were observed. These reductions were not associated with hypotensive symptoms in the vast majority of patients. Appropriate clinical advice should be given to patients when they are treated with antihypertensive medications and tadalafil.
Alpha adrenergic blockers: In two clinical pharmacology studies, no significant decreases in blood pressure were observed when tadalafil was co-administered to subjects taking the selective alpha [1A]-adrenergic blocker, tamsulosin.
When tadalafil was co-administered to healthy subjects taking doxazosin (4-8 mg daily), an alpha 1-adrenergic blocker, there was an augmentation of the blood-pressure-lowering effect of doxazosin. The number of patients with potentially clinically significant standing-blood-pressure decreases was greater for the combination. In these clinical pharmacology studies there were symptoms associated with the decrease in blood pressure including syncope.
Tadalafil did not affect alcohol concentrations, and alcohol did not affect tadalafil concentrations. At high doses of alcohol (0.7 g/kg), the addition of tadalafil did not induce statistically significant mean blood pressure decreases. In some subjects, postural dizziness and orthostatic hypotension were observed. When tadalafil was administered with lower doses of alcohol (0.6 g/kg), hypotension was not observed and dizziness occurred with similar frequency to alcohol alone.
Tadalafil had no clinically significant effect on the pharmacokinetics or pharmacodynamics of theophylline, a CYP1A2 substrate.
Ritonavir (200 mg twice daily), an inhibitor of CYP3A4, 2C9, 2C19, and 2D6, increased tadalafil single-dose exposure (AUC) by 124% with no change in Cmax. Although specific interactions have not been studied, other HIV protease inhibitors, such as saquinavir, and other CYP3A4 inhibitors, such as erythromycin and itraconazole, would likely increase tadalafil exposure.
A selective CYP3A4 inducer, rifampicin (600 daily), reduced tadalafil single-dose exposure (AUC) by 88% and Cmax by 46%, relative to the AUC and Cmax values for tadalafil alone. It can be expected that concomitant administration or other CYP3A4 inducers will also decrease plasma concentrations of tadalafil.
Simultaneous administration of an antacid (magnesium hydroxide/aluminum hydroxide) and tadalafil reduced the apparent rate of absorption of tadalafil without altering exposure (AUC) to tadalafil.
An increase in gastric pH resulting from administration of nizatidine, an H2 antagonist had no significant effect on tadalafil pharmacokinetics.
Effects of tadalafil on other medicinal products: In clinical studies, tadalafil was shown to augment the hypotensive effects of nitrates. Therefore, administration of tadalafil to patients who are using any form of organic nitrate is contraindicated (see Contraindications).
Tadalafil is not expected to cause clinically significant inhibition or induction of the clearance of drugs metabolised by CYP450 isoforms. Studies have confirmed that tadalafil does not inhibit or induce CYP450 isoforms, including CYP3A4, CYP1A2, CYP2D6, CYP2E1, CYP2C19, and CYP2C9.
Tadalafil had no clinically significant effect on exposure (AUC) to S-warfarin or R-warfarin (CYP2C9 substrate), nor did tadalafil affect changes in prothrombin time induced by warfarin.
Tadalafil did not potentiate the increase in bleeding time caused by acetyl salicylic acid.
Antihypertensive medications: Tadalafil has systemic vasodilatory properties and may augment the blood pressure lowering effects of antihypertensive agents. Additionally, in patients taking multiple antihypertensive agents whose hypertension was not well controlled, greater reductions in blood pressure were observed. These reductions were not associated with hypotensive symptoms in the vast majority of patients. Appropriate clinical advice should be given to patients when they are treated with antihypertensive medications and tadalafil.
Alpha adrenergic blockers: In two clinical pharmacology studies, no significant decreases in blood pressure were observed when tadalafil was co-administered to subjects taking the selective alpha [1A]-adrenergic blocker, tamsulosin.
When tadalafil was co-administered to healthy subjects taking doxazosin (4-8 mg daily), an alpha 1-adrenergic blocker, there was an augmentation of the blood-pressure-lowering effect of doxazosin. The number of patients with potentially clinically significant standing-blood-pressure decreases was greater for the combination. In these clinical pharmacology studies there were symptoms associated with the decrease in blood pressure including syncope.
Tadalafil did not affect alcohol concentrations, and alcohol did not affect tadalafil concentrations. At high doses of alcohol (0.7 g/kg), the addition of tadalafil did not induce statistically significant mean blood pressure decreases. In some subjects, postural dizziness and orthostatic hypotension were observed. When tadalafil was administered with lower doses of alcohol (0.6 g/kg), hypotension was not observed and dizziness occurred with similar frequency to alcohol alone.
Tadalafil had no clinically significant effect on the pharmacokinetics or pharmacodynamics of theophylline, a CYP1A2 substrate.
Caution For Usage
Instructions for use and handling: No special requirements.
Storage
Store at a temperature not exceeding 30°C. Store in the original package.
Shelf life: 3 years.
Shelf life: 3 years.
Action
Pharmacotherapeutic group: Drugs used in erectile dysfunction.
Pharmacology: Pharmacodynamics: Tadalafil is a potent, selective, reversible inhibitor of cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase type 5 (PDE5). When sexual stimulation causes the local release of nitric oxide, inhibition of PDE5 by tadalafil produces increased levels of cGMP in the corpus cavernosum. This results in smooth muscle relaxation and inflow of blood into the penile tissues, thereby producing an erection. Tadalafil has no effect in the absence of sexual stimulation.
Studies in vitro have shown that tadalafil is a selective inhibitor of PDE5. PDE5 is an enzyme found in corpus cavernosum smooth muscle, vascular and visceral smooth muscle, skeletal muscle, platelets, kidney, lung, and cerebellum. The effect of tadalafil is more potent on PDE5 than on other phosphodiesterases. Tadalafil is >10,000-fold more potent for PDE5 than for PDE1, PDE2, PDE4, and PDE7 enzymes which are found in the heart, brain, blood vessels, liver, leukocytes, skeletal muscle and other organs. Tadalafil is >10,000-fold more potent for PDE5 than for PDE3, an enzyme found in the heart and blood vessels. This selectivity for PDE5 over PDE3 is important because PDE3 is an enzyme involved in cardiac contractility. Additionally, tadalafil is approximately 700-fold more potent for PDE5 than for PDE6, an enzyme which is found in the retina and is responsible for phototransduction. Tadalafil is also >9,000-fold more potent for PDE5 than for PDE7, 8, 9, and 10 and 14-fold more potent for PDE5 than for PDE11. The tissue distribution and physiological effects of the inhibition of PDE8 through PDE11 have not been elucidated.
Two clinical studies were conducted in 571 patients in an at-home setting to define the period of responsiveness to tadalafil. Tadalafil demonstrated statistically significant improvement in erectile function and the ability to have successful sexual intercourse up to 36 hours following dosing, as well as patients' ability to attain and maintain erections for successful intercourse compared to placebo as early as 16 minutes following dosing. Sexual Encounter Profile (SEP) diary data collected in clinical studies supports this period of responsiveness. In these studies patients were free to choose the time interval between dose administration and the time of sexual attempts.
Tadalafil administered to healthy subjects produced no significant difference compared to placebo in supine systolic and diastolic blood pressure (mean maximal decrease of 1.6/0.8 mmHg, respectively), in standing systolic and diastolic blood pressure (mean maximal decrease of 0.2/4.6 mmHg, respectively), and no significant change in heart rate. When tadalafil and certain oral antihypertensive medications were assessed in drug interaction studies, tadalafil did not result in clinically significant augmentation of the antihypertensive effects of those medications (see Interactions).
In a study to assess the effects of tadalafil on vision, no impairment of colour discrimination (blue/green) was detected using the Farnsworth-Munsell 100-hue test. This finding is consistent with the low affinity of tadalafil for PDE6 compared to PDE5. In addition, no effects were observed on visual acuity, electroretinograms, intraocular pressure, or pupillometry. Across all clinical studies, reports of changes in colour vision were rare (<0.1%).
Tadalafil at doses of 2 to 100 mg has been evaluated in 16 clinical studies involving 3250 patients, including patients with erectile dysfunction of various severities (mild, moderate, severe), etiologies, ages (range 21-86 years), and ethnicities. Most patients reported erectile dysfunction of at least 1 year in duration. In the primary efficacy studies of general populations, 81% of patients reported that tadalafil improved their erections. Also, patients with erectile dysfunction in all severity categories reported improved erections while taking tadalafil (86%, 83% and 72% for mild, moderate, and severe, respectively). In the primary efficacy studies, 75% of intercourse attempts were successful in tadalafil-treated patients.
Studies on Spermatogenesis: Three studies were conducted in men to assess the potential effect on spermatogenesis of tadalafil 10 mg (one 6-month study) and 20 mg (one 6-month and one 9-month study) administered daily. There were no adverse effects on sperm morphology or sperm motility in any of the three studies. In the study of 10 mg tadalafil for 6 months and the study of 20 mg tadalafil for 9 months, results showed a decrease in mean sperm concentrations relative to placebo. This effect was not seen in the study of 20 mg tadalafil taken for 6 months. In the 9-month study, decreases in sperm concentration were associated with higher ejaculatory frequency. Ejaculation frequency was not assessed in the 6 month studies. In addition there was no adverse effect on mean concentrations of reproductive hormones, testosterone, luteinizing hormone or follicle stimulating hormone with either 10 or 20 mg of tadalafil compared to placebo.
Pharmacokinetics: Absorption: Tadalafil is rapidly absorbed after oral administration and the mean maximum observed plasma concentration (Cmax) is achieved at a medium time of 2 hours after dosing. 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 may be taken with or without food. The time of dosing (morning versus evening) had no clinically relevant effects on the rate and extent of absorption.
Distribution: The mean volume of distribution is approximately 63 L, indicating that tadalafil is distributed into tissues. At therapeutic concentrations, 94% of tadalafil in plasma is bound to proteins. Protein binding is not affected by impaired renal function.
Less than 0.0005% of the administered dose appeared in the semen of healthy subjects.
Biotransformation: Tadalafil is predominantly metabolised by the cytochrome P450 (CYP) 3A4 isoform. The major circulating metabolite is the methylcatechol glucuronide. This metabolite is at least 13,000-fold less potent than tadalafil for PDE5. Consequently, it is not expected to be clinically active at observed metabolite concentrations.
Elimination: The mean oral clearance for tadalafil is 2.5 l/h and the mean half-life is 17.5 hours in healthy subjects. Tadalafil is excreted predominantly as inactive metabolites, mainly in the faeces (approximately 61% of the dose) and to a lesser extent in the urine (approximately 36% of the dose).
Linearity/non-Linearity: Tadalafil pharmacokinetics in healthy subjects are linear with respect to time and dose. Over a dose range of 2.5 to 20 mg, exposure (AUC) increases proportionally with dose. Steady-state plasma concentrations are attained within 5 days of once-daily dosing.
Pharmacokinetics determined with a population approach in patients with erectile dysfunction are similar to pharmacokinetics in subjects without erectile dysfunction.
Special Populations: Elderly: Healthy elderly subjects (65 years or over), had a lower oral clearance of tadalafil, resulting in 25% higher exposure (AUC) relative to healthy subjects aged 19 to 45 years. This effect of age is not clinically significant and does not warrant a dose adjustment.
Renal insufficiency: In subjects with renal insufficiency, including those on hemodialysis, tadalafil exposure AUC was higher than in healthy subjects.
Hepatic insufficiency: Tadalafil exposure (AUC) in subjects with mild and moderate hepatic impairment (Child-Pugh Class A and B) is comparable to exposure in healthy subjects. No data are available in patients with severe hepatic impairment (Child-Pugh Class C).
Patients with diabetes: Tadalafil exposure (AUC) in patients with diabetes was approximately 19% lower than the AUC value for healthy subjects. This difference in exposure does not warrant a dose adjustment.
Toxicology: Preclinical safety data: Preclinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, genotoxicity, carcinogenic potential, toxicity to reproduction.
There was no impairment of fertility in male and female rats. In dogs given tadalafil daily for 6 to 12 months at doses of 25 mg/kg/day and above, there were alterations to these seminiferous tubular epithelium that resulted in a decrease in spermatogenesis in some dogs (see Pharmacodynamics previously).
Pharmacology: Pharmacodynamics: Tadalafil is a potent, selective, reversible inhibitor of cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase type 5 (PDE5). When sexual stimulation causes the local release of nitric oxide, inhibition of PDE5 by tadalafil produces increased levels of cGMP in the corpus cavernosum. This results in smooth muscle relaxation and inflow of blood into the penile tissues, thereby producing an erection. Tadalafil has no effect in the absence of sexual stimulation.
Studies in vitro have shown that tadalafil is a selective inhibitor of PDE5. PDE5 is an enzyme found in corpus cavernosum smooth muscle, vascular and visceral smooth muscle, skeletal muscle, platelets, kidney, lung, and cerebellum. The effect of tadalafil is more potent on PDE5 than on other phosphodiesterases. Tadalafil is >10,000-fold more potent for PDE5 than for PDE1, PDE2, PDE4, and PDE7 enzymes which are found in the heart, brain, blood vessels, liver, leukocytes, skeletal muscle and other organs. Tadalafil is >10,000-fold more potent for PDE5 than for PDE3, an enzyme found in the heart and blood vessels. This selectivity for PDE5 over PDE3 is important because PDE3 is an enzyme involved in cardiac contractility. Additionally, tadalafil is approximately 700-fold more potent for PDE5 than for PDE6, an enzyme which is found in the retina and is responsible for phototransduction. Tadalafil is also >9,000-fold more potent for PDE5 than for PDE7, 8, 9, and 10 and 14-fold more potent for PDE5 than for PDE11. The tissue distribution and physiological effects of the inhibition of PDE8 through PDE11 have not been elucidated.
Two clinical studies were conducted in 571 patients in an at-home setting to define the period of responsiveness to tadalafil. Tadalafil demonstrated statistically significant improvement in erectile function and the ability to have successful sexual intercourse up to 36 hours following dosing, as well as patients' ability to attain and maintain erections for successful intercourse compared to placebo as early as 16 minutes following dosing. Sexual Encounter Profile (SEP) diary data collected in clinical studies supports this period of responsiveness. In these studies patients were free to choose the time interval between dose administration and the time of sexual attempts.
Tadalafil administered to healthy subjects produced no significant difference compared to placebo in supine systolic and diastolic blood pressure (mean maximal decrease of 1.6/0.8 mmHg, respectively), in standing systolic and diastolic blood pressure (mean maximal decrease of 0.2/4.6 mmHg, respectively), and no significant change in heart rate. When tadalafil and certain oral antihypertensive medications were assessed in drug interaction studies, tadalafil did not result in clinically significant augmentation of the antihypertensive effects of those medications (see Interactions).
In a study to assess the effects of tadalafil on vision, no impairment of colour discrimination (blue/green) was detected using the Farnsworth-Munsell 100-hue test. This finding is consistent with the low affinity of tadalafil for PDE6 compared to PDE5. In addition, no effects were observed on visual acuity, electroretinograms, intraocular pressure, or pupillometry. Across all clinical studies, reports of changes in colour vision were rare (<0.1%).
Tadalafil at doses of 2 to 100 mg has been evaluated in 16 clinical studies involving 3250 patients, including patients with erectile dysfunction of various severities (mild, moderate, severe), etiologies, ages (range 21-86 years), and ethnicities. Most patients reported erectile dysfunction of at least 1 year in duration. In the primary efficacy studies of general populations, 81% of patients reported that tadalafil improved their erections. Also, patients with erectile dysfunction in all severity categories reported improved erections while taking tadalafil (86%, 83% and 72% for mild, moderate, and severe, respectively). In the primary efficacy studies, 75% of intercourse attempts were successful in tadalafil-treated patients.
Studies on Spermatogenesis: Three studies were conducted in men to assess the potential effect on spermatogenesis of tadalafil 10 mg (one 6-month study) and 20 mg (one 6-month and one 9-month study) administered daily. There were no adverse effects on sperm morphology or sperm motility in any of the three studies. In the study of 10 mg tadalafil for 6 months and the study of 20 mg tadalafil for 9 months, results showed a decrease in mean sperm concentrations relative to placebo. This effect was not seen in the study of 20 mg tadalafil taken for 6 months. In the 9-month study, decreases in sperm concentration were associated with higher ejaculatory frequency. Ejaculation frequency was not assessed in the 6 month studies. In addition there was no adverse effect on mean concentrations of reproductive hormones, testosterone, luteinizing hormone or follicle stimulating hormone with either 10 or 20 mg of tadalafil compared to placebo.
Pharmacokinetics: Absorption: Tadalafil is rapidly absorbed after oral administration and the mean maximum observed plasma concentration (Cmax) is achieved at a medium time of 2 hours after dosing. 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 may be taken with or without food. The time of dosing (morning versus evening) had no clinically relevant effects on the rate and extent of absorption.
Distribution: The mean volume of distribution is approximately 63 L, indicating that tadalafil is distributed into tissues. At therapeutic concentrations, 94% of tadalafil in plasma is bound to proteins. Protein binding is not affected by impaired renal function.
Less than 0.0005% of the administered dose appeared in the semen of healthy subjects.
Biotransformation: Tadalafil is predominantly metabolised by the cytochrome P450 (CYP) 3A4 isoform. The major circulating metabolite is the methylcatechol glucuronide. This metabolite is at least 13,000-fold less potent than tadalafil for PDE5. Consequently, it is not expected to be clinically active at observed metabolite concentrations.
Elimination: The mean oral clearance for tadalafil is 2.5 l/h and the mean half-life is 17.5 hours in healthy subjects. Tadalafil is excreted predominantly as inactive metabolites, mainly in the faeces (approximately 61% of the dose) and to a lesser extent in the urine (approximately 36% of the dose).
Linearity/non-Linearity: Tadalafil pharmacokinetics in healthy subjects are linear with respect to time and dose. Over a dose range of 2.5 to 20 mg, exposure (AUC) increases proportionally with dose. Steady-state plasma concentrations are attained within 5 days of once-daily dosing.
Pharmacokinetics determined with a population approach in patients with erectile dysfunction are similar to pharmacokinetics in subjects without erectile dysfunction.
Special Populations: Elderly: Healthy elderly subjects (65 years or over), had a lower oral clearance of tadalafil, resulting in 25% higher exposure (AUC) relative to healthy subjects aged 19 to 45 years. This effect of age is not clinically significant and does not warrant a dose adjustment.
Renal insufficiency: In subjects with renal insufficiency, including those on hemodialysis, tadalafil exposure AUC was higher than in healthy subjects.
Hepatic insufficiency: Tadalafil exposure (AUC) in subjects with mild and moderate hepatic impairment (Child-Pugh Class A and B) is comparable to exposure in healthy subjects. No data are available in patients with severe hepatic impairment (Child-Pugh Class C).
Patients with diabetes: Tadalafil exposure (AUC) in patients with diabetes was approximately 19% lower than the AUC value for healthy subjects. This difference in exposure does not warrant a dose adjustment.
Toxicology: Preclinical safety data: Preclinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, genotoxicity, carcinogenic potential, toxicity to reproduction.
There was no impairment of fertility in male and female rats. In dogs given tadalafil daily for 6 to 12 months at doses of 25 mg/kg/day and above, there were alterations to these seminiferous tubular epithelium that resulted in a decrease in spermatogenesis in some dogs (see Pharmacodynamics previously).
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Drugs for Erectile Dysfunction & Ejaculatory Disorders
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