Torfil 2.5/Torfil 10/Torfil 20

Tadalafil.

Each film-coated Tablet contains: Tadalafil 2.5 mg/10 mg/20 mg.
Torfil 2.5: Tadalafil (Torfil 2.5) 2.5 mg Film-Coated Tablet is a light orange-colored, oval-shaped, biconvex beveled edge, film-coated tablet with debossing "A9" on one side and "2.5" on other side.
Torfil 10: Tadalafil (Torfil 10) 10 mg Film-Coated Tablet is a yellow-colored, oval-shaped, biconvex beveled edge, film-coated tablet with debossing "A15" on one side and "10" on other side.
Torfil 20: Tadalafil (Torfil 20) 20 mg Film-Coated Tablet is a yellow-colored, oval-shaped, biconvex beveled edge, film-coated tablet with debossing "A16" on one side and "20" on other side.

Pharmacology: Pharmacodynamics: Mechanism of action: Sexual stimulation initiates the release of nitric oxide (NO) from the nerve terminals and endothelial cells, which stimulates synthesis of cyclic GMP in smooth muscles causing the relaxation of the penile arteries and corpus cavernosum and leads to penile erection. Tadalafil inhibits phosphodiesterase type 5 (PDE5) and enhances erectile function by increasing amount of cGMP. Because sexual stimulation is required to initiate the local release of nitric oxide, the inhibition of PDE5 by tadalafil has no effect in the absence of sexual stimulation. The effect of PDE5 inhibition on cGMP concentration in the corpus cavernosum and pulmonary arteries is also observed in the smooth muscle of the prostate, the bladder and their vascular supply. The mechanism of BPH has not been established. PDE5 is found in the smooth muscle of the corpus cavernosum, prostate, and bladder as well as in vascular and visceral smooth muscle, skeletal muscle, urethra, platelets, kidney, lung, cerebellum, heart, liver, testis, seminal vesicle, and pancreas.
Pharmacokinetics: Absorption: After single oral-dose administration, the maximum observed plasma concentration (Cmax) of tadalafil is achieved between 30 minutes and 6 hours (median time of 2 hours). Absolute bioavailability of tadalafil following oral dosing has not been determined. The rate and extent of absorption of tadalafil are not influenced by food; thus, tadalafil tablets may be taken with or without food.
Distribution: The mean apparent volume of distribution following oral administration is approximately 63 L, indicating that tadalafil is distributed into tissues. At therapeutic concentrations, 94% of tadalafil in plasma is bound to proteins. Less than 0.0005% of the administered dose appeared in the semen of healthy subjects.
Metabolism: Tadalafil is predominantly metabolized by CYP3A4 to a catechol metabolite. The catechol metabolite undergoes extensive methylation and glucuronidation to form the methylcatechol and methylcatechol glucuronide conjugate, respectively. The major circulating metabolite is the methylcatechol glucuronide. Methylcatechol concentrations are less than 10% of glucuronide concentrations. In vitro data suggests that metabolites are not expected to be pharmacologically active at observed metabolite concentrations.
Excretion: The mean oral clearance for tadalafil is 2.5 L/hr and the mean terminal half-life is 17.5 hours in healthy subjects. Tadalafil is excreted predominantly as metabolites, mainly in the feces (approximately 61% of the dose) and to a lesser extent in the urine (approximately 36% of the dose).
Special Populations: Geriatric: Healthy male elderly subjects (65 years or over) had 25% higher exposure (AUC) with no effect on Cmax relative to that observed in healthy subjects 19 to 45 years of age. No dose adjustment required based on age alone. However, greater sensitivity to medications in some older individuals should be considered.
Torfil 2.5: Patients with Diabetes Mellitus: In male patients with diabetes mellitus after a 10 mg tadalafil dose, exposure (AUC) was reduced approximately 19% and Cmax was 5% lower than that observed in healthy subjects. No dose adjustment required.
Patients with BPH: In patients with BPH following single and multiple-doses of 20 mg tadalafil, no statistically significant differences in exposure (AUC and Cmax) were observed between elderly (70 to 85 years) and younger (≤60 years of age) subjects. No dose adjustment required.
Torfil 10/Torfil 20: Renal impairment: Exposure to tadalafil is much higher in patients with renal impairment as compared to healthy subjects.
Hepatic Impairment: No dosage adjustment required for patients with mild to moderate hepatic impairment. No data available for patients with severe hepatic impairment. Patients with diabetes: Exposure of tadalafil is lower in diabetic patients compared in healthy subjects.

Torfil 2.5: Tadalafil is indicated for the treatment of erectile dysfunction. Tadalafil is indicated for the treatment of the signs and symptoms of benign prostatic hyperplasia in adult males. It is used for the treatment of erectile dysfunction and the signs and symptoms of benign prostatic hyperplasia in adult males.
Torfil 10/Torfil 20: Indicated for the treatment of erectile dysfunction in adult males. In order for Tadalafil to be effective for the treatment of erectile dysfunction, sexual stimulation is required.

Torfil 2.5: Tablet should be swallowed whole and without regards to food. The recommended dose is 5 mg taken one tablet per day at the same time every day without regard to timing of sexual activity for the treatment of Erectile dysfunction and benign prostatic hyperplasia. When therapy for BPH is initiated with finasteride, the recommended dose is 5 mg once daily for 26 weeks.
Renal impairment: Tadalafil is not recommended for daily use in treatment of erectile dysfunction and benign prostatic hyperplasia with patients in which creatinine clearance is less than 30mL/min. or on hemodialysis. As for patients with creatinine clearance of less than 30mL/min. to 50mL/min, the recommended dose for treatment of benign prostatic hyperplasia and erectile dysfunction is 5 mg based on the individual's response.
Hepatic Impairment: There is no established study regarding the use of tadalafil in patients with mild to moderate hepatic impairment (Child Pugh Class A or B). Therefore, caution is advised if daily use is prescribed to these patients. The use of tadalafil in patients with severe hepatic impairment (Child Pugh Class C) is not recommended.
Elderly: No dosage adjustment required.
Children: Tadalafil is not recommended for use in individuals below 18 years of age.
Torfil 10/Torfil 20: 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 engage in sexual activity at different time points to determine their own optimal window of responsiveness. The maximum dosing frequency is one tablet per day taken without regards to food.
Elderly Men: Dose adjustments are not required in elderly patients.
Renal Impairment: Dose adjustments are not required in patients with mild to moderate renal impairment.
Hepatic Impairment: Dose adjustments are not required in patients with hepatic impairment. However, caution is advised when Tadalafil is used in patients with severe hepatic impairment (Child-Pugh Class C).
Diabetes: Dose adjustments are not required in diabetic patients.
Children: Tadalafil is not recommended for use in individuals below 18 years of age.

Single doses 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.

It is contraindicated in patients with known hypersensitivity to Tadalafil and to any of its excipients. Administration of Tadalafil is also contraindicated in patients who are taking any form of organic nitrates as it is known to increase the hypotensive effects of the nitrate.
Torfil 2.5: Tadalafil is not recommended for concomitant use with guanylate cyclase (GC) stimulator due to potentiation of the hypotensive effects of GC stimulator.

2.5 mg: Evaluation of erectile dysfunction and benign prostatic hyperplasia should include an appropriate medical assessment to identify potential underlying causes as well as treatment options.
Patients with Cardiovascular Disease: Treatments for erectile dysfunction, including tadalafil is not recommended in patients with cardiac diseases for whom sexual activity is inadvisable. PDE5 inhibitors have vasodilatory properties which leads to transient decreases in blood pressure.
Torfil 2.5: In the event when a patient who has taken tadalafil needs nitrate administration deemed medically necessary for life-threatening situation, at least 48 hours must elapse after the last dose of tadalafil before nitrate is considered. Patients with severely impaired autonomic control of blood pressure may be sensitive to the effects of vasodilators, including PDE5 inhibitors.
Torfil 10/Torfil 20: Physicians must consider if their patients pose risk to such vasodilatory effects. Sexual activity poses serious cardiac risks to patients with pre-existing cardiovascular diseases.
Prolonged erection and Priapism: Torfil 2.5: Cases of prolonged erection lasting greater than 4 hours and priapism (painful erection lasting greater than 6 hours) have been associated with the use of PDE5 inhibitors, including tadalafil. Patients with erection lasting for 4 hours or more must seek immediate medical attention. If neglected, it may result to penile tissue damage leading to permanent loss of potency. Caution must be exercised with the use of tadalafil in patients present with risk factors to priapism (sickle cell anemia, multiple myeloma, or leukemia) and in patients with anatomical deformation of the penis (angulation, cavernosal fibrosis or Peyronie's disease).
Torfil 10/Torfil 20: Cases of priapism have been associated with PDE5 inhibitors, including tadalafil. Patients with erection lasting for 4 hours or more must seek immediate medical attention. If neglected, it may result to penile tissue damage leading to permanent loss of potency. Caution must be exercised with the use of tadalafil in patients present with risk factors to priapism (sickle cell anemia, multiple myeloma, or leukemia) and in patients with anatomical deformation of the penis (angulation, cavernosal fibrosis or Peyronie's disease).
Combination with Other Agent for Treatment of Erectile dysfunction: Determination of potential underlying cause and application of appropriate treatment after thorough medical assessment must be included in evaluating erectile dysfunction. There are no established studies regarding the combination of tadalafil with other agents for treatment of erectile dysfunction. Therefore, co-administration is not recommended.
Torfil 2.5: Alpha-blockers blockers and Antihypertensives: Caution is advised when PDE5 inhibitors are co-administered with alpha-blockers. Both substances are vasodilators with blood-pressure lowering effects, this may lead to symptomatic hypotension (e.g., fainting). For patients using tadalafil for erectile dysfunction, ensure that patient is stable on alpha-blocker therapy before administration of Tadalafil to prevent risk of developing symptomatic hypotension. Use of the lowest recommended dose is advised. For patients with BPH, concomitant use of Tadalafil and alpha-blocker is not recommended.
Alcohol: Alcohol and Tadalafil both act as mild vasodilators. When taken in combination, blood pressure-lowering effect of each substance may be increased. This may also increase risk of orthostatic signs and symptoms (increased heart rate, decreased standing BP, dizziness, and headache).
Visual Impairment: Rare reports of sudden loss of vision have been associated with temporal use of PDE5 inhibitors, including Tadalafil. Patient must be advised to discontinue medication and seek medical attention if vision impairment occurs as this may be a sign of NAION. NAION (non-arteritic anterior ischemic optic neuropathy) is a cause of decreased vision including permanent loss of vision. In the event of a sudden loss of vision. Patients with known hereditary degenerative retinal disorders (e.g., retinitis pigmentosa,) are contraindicated with the use of tadalafil.
Sudden Hearing Loss: Sudden hearing loss usually accompanied by tinnitus and dizziness have been reported with the temporal use of PDE5 inhibitors. Patient should discontinue medication and seek medical attention if this occurs.
Sexually Transmitted Disease: The use of tadalafil offers no protection against sexually transmitted disease.
Bleeding: Caution is advised in patients with bleeding disorders or significant active peptic ulceration.
Patient with Other Urological Conditions: In some cases, Benign Prostatic Hyperplasia and prostate cancer may coexist. Consideration is given to patients with other urological conditions prior to initiating treatment for BPH as that may cause similar symptoms.
Renal Impairment: Tadalafil is not recommended for patients with creatinine clearance less than 30 mL/min.
Hepatic Impairment: Caution is advised for patients with mild to moderate hepatic impairment if prescribed with once daily use of tadalafil. It is not recommended in patient with severe hepatic impairment.
Torfil 10/Torfil 20: Alpha-adrenergic Receptors Blockers: Co-administration of tadalafil with alpha-1 blockers such as doxazosin may lead to symptomatic hypotension.
Non-arteritic Anterior Ischemic Optic Neuropathy (NAION): NAION is a cause of decreased vision including permanent loss of vision. In the event of a sudden loss of vision, patients should be advised by their physician to stop use of tadalafil and must seek medical attention immediately.
Combination with Other PDE5 Inhibitors: Tadalafil has systemic vasodilatory properties which may result in transient decreases in blood pressure.
Hepatic Impairment: No data are available in patients with severe hepatic impairment (Child-Pugh Class C).
Effects on ability to drive and use machine: Tadalafil has negligible influence on the ability to drive or 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 using machines.

Tadalafil is not indicated for use by women. There are no studies for the use of Tadalafil in pregnant women.

Torfil 2.5: The most commonly reported adverse events associated with the use of tadalafil were headache, upper abdominal pain, and myalgia. These adverse events were mild to moderate, transient and decreased with continued dosing. Other common adverse events were gastroesophageal reflux disease, nausea, vomiting, arthralgia, and muscle spasm. The table as follows shows other adverse event that were minor, those with no plausible relation to drug use, and reports were too imprecise to be meaningful. (See Table 1.)

Click on icon to see table/diagram/image

Torfil 10/Torfil 20: The most commonly reported adverse events associated with the use of tadalafil were headache and dyspepsia. These adverse events were mild to moderate, transient and decreased with continued dosing. Other common adverse events were myalgia, back pain, flushing and nasal congestion. Uncommon adverse events reported were swelling of eyelids, sensations described as eye pain, conjunctival hyperaemia, dyspnea, and dizziness. In post-marketing surveillance, the following adverse events were reported. (See Table 2.)

Click on icon to see table/diagram/image

Antacids: Concomitant use of antacids (e.g., Magnesium hydroxide and/or Aluminum hydroxide) and tadalafil reduces the rate of absorption of tadalafil without modifying tadalafil exposure.
H2 Antagonists: Use of H2 antagonist has no significant effect on the pharmacokinetics of tadalafil; Co-administration of Tadalafil and Nizatidine reduces the gastric pH.
Nitrates: Torfil 2.5: Administration of Tadalafil is contraindicated in patients who are taking any form of organic nitrates as it is known to increase the hypotensive effects of the nitrate. In a patient whose taken tadalafil, where administration of nitrate is deemed medically necessary in a life-threatening situation, at least 48 hours should elapse after the last dose of Tadalafil before nitrate administration is considered.
Torfil 10/Torfil 20: Concomitant use of tadalafil with any other organic nitrates is contraindicated as it may augment hypotensive effects of nitrates.
Warfarin: There is no significant effect on the exposure to warfarin nor did tadalafil affect changes in the prothrombin time induced by warfarin.
HIV protease inhibitor: Torfil 2.5: Ritonavir, an inhibitor of CYP 3A4, CYP2C9, CYP2C19, and CYP2D6, increased tadalafil exposure. Other HIV protease inhibitors would likely increase tadalafil exposure.
Torfil 10/Torfil 20: HIV protease inhibitors such as saquinavir, erythromycin, and itraconazole would likely decrease tadalafil exposure.
Aspirin: Tadalafil did not potentiate the increase in bleeding time caused by aspirin.
Antihypertensives: Torfil 2.5: PDE5 inhibitors, including tadalafil, are mild vasodilators. Tadalafil potentiates the blood pressure-lowering effects of selected antihypertensive agents (e.g., amlodipine, angiotensin II receptor blockers, enalapril, and metoprolol) and small reduction in blood pressure occurred.
Torfil 10/Torfil 20: Co-administration of tadalafil with alpha-adrenergic receptor blockers may augment blood pressure lowering effects of anti-hypertensive agents (e.g. doxazosin) which may lead to systemic hypotension.
Alcohol: Torfil 2.5: When mild vasodilators are taken in combination, blood pressure-lowering effects of each individual compound may be increased. Substantial consumption of alcohol (e.g., 5 units or greater) in combination with Tadalafil can increase the potential for orthostatic signs and symptoms, including increase in heart rate, decrease in standing blood pressure, dizziness, and headache. Tadalafil did not affect alcohol plasma concentration and alcohol did not affect tadalafil plasma concentrations.
Torfil 10/Torfil 20: Tadalafil has no effect in the alcohol concentration and vice versa. Postural dizziness and orthostatic hypotension were observed but can be prevented my reducing dose of alcohol.
Theophylline: Tadalafil has no significant effect on the pharmacokinetics and pharmacodynamics of theophylline.
Torfil 2.5: Cytochrome P450 Inhibitors: Tadalafil is predominantly metabolized in the liver by CYP3A4. CYP 3A4 inhibitors (e.g., Ketoconazole, erythromycin, itraconazole, and grapefruit juice) increases tadalafil exposure.
Cytochrome P450 Inducers: Co-administration with CYP3A4 inducers (e.g., Rifampicin, carbamazepine, phenytoin and phenobarbital) reduces tadalafil exposure.
Midazolam and Lovastatin: Tadalafil had no significant effect on exposure to midazolam and lovastatin.
P-glycoprotein (e.g., Digoxin): Tadalafil had no significant effect on the pharmacokinetics of digoxin.
Torfil 10/Torfil 20: CYP3A4 Inhibitors: Co-administration with CYP3A4 inhibitors such as ketoconazole, ritonavir, saquinavir, erythromycin, and itraconazole increases tadalafil exposure.
CYP3A4 Inducers: Co-administration with CYP3A4 inducers (e.g. Rifampicin) reduces tadalafil exposure.

Store at temperatures not exceeding 30°C.

Drugs for Erectile Dysfunction & Ejaculatory Disorders / Drugs for Bladder & Prostate Disorders

G04BE08 - tadalafil ; Belongs to the class of drugs used in erectile dysfunction.

Rx