SNAFI

SNAFI® 20 mg TABLETS Tadalafil

COMPOSITION	Each tabletcontains 20 mg tadalafil For excipients Tablet core: lactose monohydrate, croscarmellose sodium, hydroxypropylcellulose, microcrystalline cellulose, sodium lauryl sulfate, magnesium stearate.

INDICATIONS	Treatment of erectile dysfunction. In order for Snafi to be effective, sexual stimulation is required.

pharmacoDYNAMIC properties	Pharmacotherapeutic group: Drugs used in erectile dysfunction. 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. Snafi administered to healthy subjects produced no significant difference compared to placebo in supine systolic and diastolic blood pressure or in standing systolic and diastolic blood pressure ,and no significant change in heart rate. 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 %). There were no clinically relevant effects on sperm concentration, sperm count, motility or morphology in 103 men after daily doses of 10 mg for 6 months. 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 Snafi improved their erections. Also, patients with erectile dysfunction in all severity categories reported improved erections while taking Snafi (86 %, 83 % and 72 % for mild, moderate, and severe, respectively). In the primary efficacy studies, 75 % of intercourse attempts were successful in Snafi-treated patients.

pharmacoKINETIC properties	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 Snafi 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).

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 mild (creatinine clearance 51 to 80 ml/min) or moderate (creatinine clearance 31 to 50 ml/min) renal impairment, tadalafil exposure (AUC) was higher than in healthy subjects. Tadalafil has not been studied in subjects with severe renal impairment ( creatinine clearance ≤ 30ml / min ). Hepaticin sufficiency 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 dose adjustment is required in these patients. 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. Preclinical safety data Preclinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, genotoxicity, carcinogenic potential, toxicity to reproduction.

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 Snafi to patients who are using any form of organic nitrate is contraindicated. Snafi should not be used in patients with a known hypersensitivity to tadalafil or to any of the excipients.

Special warnings and special precautions for use	Sexual activity carries a potential cardiac risk for patients with pre-existing cardiovascular disease. Therefore, treatments for erectile dysfunction, including Snafi should not be used in men with cardiac disease for whom sexual activity is inadvisable. 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 Additionally, there is no controlled clinical data on the safety or efficacy of Snafi in the following groups; if prescribed, this should be done with caution: Patients with severe renal insufficiency ( creatinine clearance ≤ 30 ml / min ) Patients with severe hepaticin sufficiency ( Child - Pugh Class C ) Priapism was not reported in clinical trials with Snafi. However, priapism has been reported with another PDE5 inhibitor, If priapism is not treated immediately, penile tissue damage and permanent loss of potency may result. Snafi 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 safety and efficacy of combinations of Snafi and other treatments for erectile dysfunction have not been studied. Therefore, the use of such combinations is not recommended.

Interaction with other medicinal products and other forms of interaction	Effects of other medicinal products on tadalafil Tadalafil is principally metabolised by CYP3A4. A selective inhibitor of CYP3A4, ketoconazole, increased tadalafil AUC by 107 % and a CYP3A4 inducer, rifampicin, reduced tadalafil AUC by 88 %, relative to the AUC values for tadalafil alone. Simultaneous administration of an antacid (magnesium hydroxide/aluminium 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 Snafi to patients who are using any form of organic nitrate is contraindicated. Snafi 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 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. In clinical pharmacology studies, the potential for tadalafil to augment the hypotensive effects of antihypertensive agents was examined. Analysis of phase 3 clinical trial data also showed no difference in adverse events in patients taking tadalafil with or without antihypertensive medications. Alcohol concentrations (mean maximum blood concentration 0.08 %) were not affected by co-administration with tadalafil. The effects of alcohol on cognitive function and on blood pressure were not augmented by tadalafil. In addition, no changes in tadalafil concentrations were seen 3 hours after co-administration with alcohol. Tadalafil had no clinically significant effect on the pharmacokinetics or pharmacodynamics of theophylline, a CYP1A2 substrate.

Pregnancy and lactation	Snafi is not indicated for use in women. There are no studies of tadalafil in pregnant women.

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 Snafi, before driving or operating machinery.

Undesirable effects	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 and dizziness are uncommon adverse events.

Posology and administration	For oral use. Use in adult men The recommended dose of Snafi is 20 mg taken prior to anticipated sexual activity and without regard to food. Efficacy of tadalafil may persist up to 24 hours post dose. The maximum recommended dosing frequency is once per day. Use in elderly men Dosage adjustments are not required in elderly patients. Dosage recommendations described in "use in adult men" apply to elderly men. Use in men with impaired renal function Dosage adjustments are not required in patients with mild or moderate renal impairment. Use in men with impaired hepatic function Dosage adjustments are not required in patients with mild to moderate hepatic impairment. Use in men with diabetes Dosage adjustments are not required in diabetic patients. Use in children Snafi should not be used in individuals below 18 years of age.

Overdose	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.

STORAGE	Shelf life: 2 years. Do not store above 30° C. Store in the original package.

PRESENTATIONS	Snafi is available as tablet 20mg formulation.