SONAGRA CAPSULE 10mg
Each capsule contains:
SONAGRA Capsule contains tadalafil, a selective, reversible inhibitor of cyclic guanosine monophosphate benzodioxol-5-yl)-2-methyl-2, 3, 6, 7, 12, 12-a-hexahydropyrazino [1’, 2’.1, 6] pyrido [3, 4-b] indole-1, 4-dione.
The molecular formula of tadalafil is C12H19N304.
Mechanism of action
Tadalafil is a selective, reversible inhibitor of cyclic guanosine inactive metabolites, mainly in the faeces (approximately 61% of the dose) monophosphate (cGMP)-specific phosphodiesterase type 5 (PDE5).
When sexual stimulations causes the local release of nitric oxide, inhibition of PDE5 by tadalafil produces increased levels of cGMP in the corpus cavemosum. 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, vascular and visceral smooth muscle, skeletal muscle, platelets, kidney, lung and cerebellum. The effect of tadalafil is more potent on PDE than on other phosphodiesterasea. Tadalafil is >10.000 fold more potent for PED5 than for PED1, PED2 and PED4, enzymes which are found in the heart, brain, blood vessels, liver, and other organs. Tadalafil is >10.000-fold more potent for PDE5 than 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.
Additional, tadalafil is approximately 700-fold more potent for PDE5 and PDE6, an enzyme which is found in the retina and is responsible for photo transduction.
Tadalafil is also <10.000-fold more potent for PDE5 than for PDE7 through PDE10.
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 24 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 and a statistically significant greater proportion of successful intercourse attempts associated with tadalafil treatment compared to placebo treatment up to and through the 12-14 hour interval following administration. 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 to placebo in supine systolic and diastolic blood pressure (mean maximal decrease of 1.6/0.8 mm Hg, respectively), in standing systolic and diastolic blood pressure (mean maximal decrease of 0.2/4.6 mm Hg, respectively) and no significant change in heart rate. When tadalafil and certain oral antihypertensive medication (including angiotensin II receptor blockers) were assessed in drug interaction studies, tadalafil did not result in clinical significant augmentation of the antihypertensive effects of those medications (see Drug Interactions). However, appropriate clinical advice should be given to patients regarding the possibility of a decrease in blood pressure when they are treated with antihypertensive medications; the administration of tadalafil to patients who are using any form of organics nitrate is contraindicated.
In a study to assess the effects of tadalafil on vision, no impairment of colour discrimination (blue/green) was detected using the Farmsworth-Munsell 100-hue test. This finding is consistent with the low affinity of tadalafil for PDE6 compared to PDE5. Across all clinical studies, report of changes in colour vision were rare (<0.1).
Two studies were conducted in men to assess the potential effect of tadalafil 10mg and 20mg administered daily for 6 months on spermatogenesis. The results of these studies demonstrate no difference from placebo with respect to the proportion of men showing a 50% or greater decrease in sperm concentration. In addition in comparison with placebo, there were no adverse effects observed with respect to mean change in sperm count, sperm morphology, or sperm motility at either dose. However, in the study of 10mg tadalafil taken daily for 6 months, results showed a decrease in mean sperm concentration relative to placebo. This effect was not seen in the study where the higher dose, 20mg tadalafil was taken daily for 6 months. In addition, there was no effect on mean concentrations of testosterone, luteinizing hormone or follicle stimulating hormone with either 10mg or 20mg of tadalafil compared to placebo. The effects of long-term daily dosing have not been established. (See PRECAUTIONS, General and Carcinogenicity/Matafenicity/Impairment of Fertility).
Tadalafil doses of 2 to 10mg has been evaluated in 16 clinical studies involving 3,250 patients, including patients with erectile dysfunction of various severities (mild, moderate, severe), aetiologies, 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 as compared to 35% with placebo. Also, patients with erectile dysfunction in all severity categories reported improved erections whilst taking tadalafil (86%, 83% and 72% for mild, moderate and severe, respectively, as compared to 45%, 42% and 19% with placebo). In the primary efficacy studies, 75% of intercourse attempts were successful in tadalafil treated patients as compared to 32% with placebo.
Tadalafil is readily absorbed after oral administration and the mean maximum observed plasma concentration (Cmax) is achieved at a median 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.
The mean volume of distribution is approximately 63 litres, 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.
Tadalafil is predominantly metabolised by the cytochrome P450 (CYP) 344 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.
The mean clearance for tadalafil is 2.5 1/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 62% of the dose) and to a lesser extent in the urine (approximately 36% of the dose).
Tadalafil pharmacokinetics in healthy subjects are linear with respect to time and dose.
Over a dose range of 2.5 to 20mg 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.
Pharmacokinetics in special populations
Geriatric: Healthy elderly subjects (65years or over) has 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.
Hepatic Impairment: In clinical studies, tadalafil exposure (AUC) in subjects with mild or moderate hepatic impairment (Child-Pugh A or B) was comparable to exposure in healthy subjects when a dose of 10mg was administered. There are no available data for doses higher than 10mg of tadalafil in patients with hepatic impairment. Insufficient data are available for subjects with severe hepatic impairment (Child-Pugh Class C). therefore, for patients with mild or moderate hepatic impairment, the maximum dose should not exceed 10mg and use in patients with severe hepatic impairment not recommended.
Renal Insufficient: In clinical studies using single dose tadalafil (5 to 10mg) tadalafil exposure (AUC) doubled in subjects with mild (creatinine clearance 51 to 80ml/min) or moderate (creatinine clearance 31 to 50ml/min) renal insufficiency in subjects with end-stage renal disease on greater proportion of successful intercourse attempts associated with haemodialysis, there was a two-fold increase in Cmax and 2.7 to 4.1 fold increase in AUC following single-dose administration of 10 or 20mg Tadalafil. Exposure to total methylcatechol (unconjugated plus glucronide) was 2-to-4-fold higher in subjects with renal impairment, compared to those with normal renal function. Haemodialysis (performed between 24 and 30 hours post-dose) contributed negligibly to tadalafil metabolite elimination. In a clinical pharmacology study (N=28) at a dose of 10mg, back pain was reported as a limiting adverse event in male patients with moderate renal impairment. At a dose of 5mg the incidence and severity of back pain was not significantly different than the general population. In patients on haemodialysis taking 10-20mg tadalafil there were no reported cases of back pain. The dose of tadalafil should be limited to 5mg not more once daily in patients with severe renal insufficiency or end-stage renal disease. A starting dose or 5mg not more than once daily is recommended for patients with moderate renal insufficiency, the maximum recommended dose is 10mg not more than once in every 48 hours. No dose adjustment is required in patients with mild renal insufficiency.
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.
Sonagra (tadalafil) capsules are indicated for the treatment of erectile dysfunction.
DOSAGE AND ADMINISTRATION
In order for tadalafil to be effective, stimulation is required.
Tadalafil is not required for use by women.
Use in adult men: The recommended dose is 10mg taken prior to anticipated sexual activity and without regard to food in those patients in whom SONAGRA 10mg does not produce an adequate effect, 20mg might be tried.
Tadalafil may improve erectile function up to 36 hours following dosing. The maximum recommended dosing frequency is once per day.
Daily use of the medication is strongly discouraged because the long-term safety after prolonged daily dosing has not been established (see PRECAUTIONS, General).
Use in elderly men: Dosage adjustments are not required in elderly patients.
Use in men with impaired renal function: No dose adjustment is required in patients with mild renal insufficiency. For patients with moderate creatinine clearance 31 to 5ml/min) renal insufficiency, a starting dose of 5mg not more than once daily is recommended and the maximum dose should be limited to 10mg not more than once in every 48 hours. For patients with severe (creatinine clearance <30ml/min) renal insufficiency on haemodialysis, the maximum recommended dose is 5mg (see PRECAUTIONS and Pharmacokinetic).
Use in men with impaired hepatic function: For patients with mild or moderate degree of hepatic impairment (Child-Pugh Class A or B) the dose of Sonagra should not exceed 10mg once daily in patients with severe hepatic impairment (Child-Pugh Class C), the use of Sonagra is not recommended (see PRECAUTIONS and Pharmacokinetics).
Use in men with diabetes: Dosage adjustment are not required in diabetic patients.
Use in children and adolescents: Sonagra should not be used in individuals below 18 years.
A medical history and physical examination should be undertaken to diagonise erectile dysfunction and determine potential underlying causes, before pharmacological treatment is considered.
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 sangulation 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. It is not known if tadalafil is effective in patients with spinal cord injuries and patients who have undergone pelvic surgery or radical non-nerve sparing prostatectomy.
The safety and efficacy of combinations of tadalafil and other treatments for erectiIe dysfunction have not been studied. Therefore, the use of such combinations is not recommended.
In dogs given tadalafil daily for 6 to 12 months at doses of 25mg/kg/day (resulting in at least a 3-fold greater exposure (range 37186) than seen in humans at a 2mg single dose) and above, there was regression of the seminiferous tubular epithelium that resulted in a decrease in spermatogenesis in some dogs. Results from two 6 month studies in volunteers suggest that this effect is unlikely in humans (see PHARMACOLOGY). The effects of longer term daily dosing have not been established. Therefore, daily use of the medication strongly discouraged.
Effects on ability to drive and use machines
Tadalafil is expected to have no or negligible influence on the ability to drive and/or use machines. No specific studies have been performed to evaluate a potential effect.
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.
Prior to initiating any treatment for erectile dysfunction, physicians should consider the cardiovascular status of their patients, since there is a degree of cardiac risk associated with sexual activity. Tadalafil has vasodilator properties, resulting in mild and transient decreases in blood pressure and as such potentiates the hypotensive effects of nitrates (see PHARMACOLOGY and Contraindications).
Serious cardiovascular events, including myocardial infarction, unstable angina pectoris, ventricular arrhythmia, strokes and transient ischemic attacks occurred during clinical studies of tadalafil. In additions, hypertension and hypotension (including postural hypotension) were also seen infrequently in clinical trials. Most of the patients in whom these events have been observed had pre-existing cardiovascular risk factors. However, it is not possible to definitely determine whether these events are related directly to these risk factors.
There is limited clinical data on the safety of tadalafil in the following groups. If prescribed, a careful benefit risk evaluation should be undertaken by the prescribing physician.
Tadalafil should be limited to 5mg not more than once daily in patients with severe renal insufficiency or end-stage renal disease. The starting dose of tadalafil in patients with a moderate degree of renal insufficiency should be 5mg not more than once daily, and the maximum dose should be limited to 10mg not more than once in every 48 hours. No dose adjustment is required in patients with mild renal insufficiency.
In patients with mild moderate hepatic impairment, the dose of tadalafil should not exceed 10mg. Because of insufficient information in patients with severe hepatic impairment use of tadalafil in this group is not recommended.
Priapism was not reported in clinical trials with tadalafil. However, priapism has been reported with another PDE5 inhibitor. Patients who experience erection 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.
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 Sonagra to patients who are using any form of organic nitrate is contraindicated.
Agents for the treatment of erectile dysfunction including Sonagra 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 and the use of tadalafil is therefore contraindicated
• Patients with myocardial infarction within the 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 uncontrollable arrhythmias, hypotension (<90/50mm Hg) or uncontrollable hypertension
• Patients with a stroke within the last 6 months
Sonagra should not be used in patients with hypersensitivity to tadalafil or to any of the excipients.
Tadalafil is not indicated for use by women. There are no studies of tadalafil in pregnant women. There was no evidence of teratogenicity, embryo toxicity or foe toxicity in rat or mice that received up to 1000mg/kg/day.
Many of the interaction studies were conducted with 10mg tadalafil, as indicated below. With regards to those interaction studies where only the 10mg tadalafil dose was used, clinically relevant interactions at higher doses cannot be completely ruled out.
Effects of other medicinal products on tadalafil: Tadalafil is principally metabolised by CYP3A4. A selective inhibitor of CYP3A4, ketoconazole, increased tadalafil AUC by 107% relative to the AUC values for tadalafil along (10mg dose). Although specific interactions have been studied, some protease inhibitors, such as ritonavir and saquinavir and other CYP3A4 inhibitors, such as erythromycin, clarithromycin, itraconazle and grapefruit juice, should be co-administered with caution as they would be expected to increase plasma concentration of tadalafil. Consequently the incidence of the undesirable effects might be increased. The role to transporters (for example, p-glycoprotein) in the disposition of tadalafil is not known. There is thus the potential of drug interaction medicated by inhibition of transporters.
A CYP3A4 inducer, rifampicin, reduced tadalafil AUC by 88% relative to the AUC values for tadalafil along (10mg dose). It can be expected that concomitant administration of other CYP3A4 inducers, such as phenobarbial, phenutone and carbamazepine will also decrease plasma concentrations of tadalafil.
Effects of tadalafil on other medicinal products: In clinical studies, tadalafil (10mg) was shown to augment the hypotensive effects of nitrates. Therefore; administration of tadatafil 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, CYP2D6, CYP2E1 and CYP2C9.
Tadalafil (10mg) had no clinically significant effect on exposure (AUC) to S-warfarin or R-warfarin (CYP2C9 substrate), nor did tadalafil affects changes in prothrombin time induced by warfarin.
Tadalafil (10mg) did not potentiate the increase in bleeding time caused by acetylsalicylic acid. In clinical pharmacology studies, the potential for tadalafil to augment the hypotensive effects of antihypertensive agents was examined. Major classes of antihypertensive agents were studied, including calcium channel blockers (amlodipine) angiotensin converting enzyme (ACE) inhibitors (enalapril), beta-adrenergic receptor blockers (metroprolol) thiazide diuretics (bendrofluazide) and angiotensin II receptor blockers (various types and doses), alone or in combination with thiazides, calcium channel blockers beta blockers and/or alpha blockers) Tadalafil (10mg except for studies with angiotensin if receptor blockers and amlodipine in which a 20mg dose was applied) had no clinically significant interaction with any of these classes. Tadalafil (10mg and 20mg) has no clinically significant effect on blood pressure changes due to tamsulosin an alpha adrenergic receptor blocking agent. In patients receiving concomitant antihypertensive medications, tadalafil 20mg may induce a blood pressure decrease, which is in general minor and not likely to be clinically relevant. Analysis of Phase 3 clinical trial data showed no difference in adverse effects in patients taking tadalafil with or without antihypertensive medication. However appropriate clinical advice should be given to patients regarding a possible decrease in blood pressure when they are treated with anti hypertensive medications.
Alcohol concentrations mean maximum blood concentrations 0.08% was not affected by co-administration with tadalafil (10mg). The effect of alcohol on cognitive function was not augmented by tadalafil (10mg) nor was the effect of alcohol on blood pressure augmented by tadalafil (20mg). In addition, no changes in tadalafil concentrations were seen 3 hours after co-administration with alcohol.
Tadalafil has been demonstrated to produce an increase in the oral bioavailability of ethinylestradiol; a similar increase may be expected with oral administration of terbutaline, although the clinical consequence of this is uncertain.
Carcinogenicity/Mutagenicity/Impairment of Fertility
Pre clinical data reveal no specific hazard for humans based on concentional studies of safety pharmacology, gentoxity, carcinogenicity potential, and toxicity to reproduction.
There was no evidence of teratogenicity, embryo toxicity or foe toxicity in rats or mice that received up to 1000mg/kg/day. In the rat pre and post natal development study, the no observed effect dose was 30mg/kg/day. In pregnant rat the AUC for calculated free drug at this dose was approximately 18 times the human AUC at a 20mg dose.
There was no impairment of fertility in male and female rats. In dogs given tadalafil daily for 6-12 months at doses of 25mg/kg/day (resulting in at least a 3-fold greater exposure range 3.7-18.6) than seen in humans given a single 20mg dose) and above, there was regression of seminiferous tubular epithelium that resulted in a decrease in spermatogenesis in some dogs. (See PRECAUTIONS, General and Pharmacology).
The most common reported adverse reactions are headache and dyspepsia.
(Common Adverse Reactions (>1/100, <1/10) dizziness (2.3% flushing 4.1%), Nasal Congestion 4.3.
Swelling of eyelids, sensation described as eye pain and conjunctiva hyperaemias are uncommon adverse reactions.
The adverse effects reported with tadalafil were transient and generally mild or moderate. Adverse effect data are limited in patients over 75 years of age.
Single dose up to 50mg have been given to healthy subjects, and multiple daily doses up to 10mg have been given to patients.
Adverse effects were similar to those seen at lower doses.
In case of overdose, standard supportive measure should be adopted as required.
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