Exilar 5

Each Film Coated Tablet Contains:

Tadalafil 5 mg

Excipients q.s.

Colour: Iron Oxide Red,

Lake of indigo carmine and lake of Ponceau 4R

Chemical Name: Pyrazino [1’,2’:1,6] pyrido[3,4-b]indole-1,4-dione,6-(1,3- benzodioxol-5-yl)-2,3,6,7,12,12a-hexahydro-2-methyl-, (6R,12aR)-

Category: Drug used in erectile dysfunction.

Description:

Tadalafil, an oral treatment for erectile dysfunction, is a selective inhibitor of cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase type 5 (PDE5). Tadalafil has the empirical formula C H N O representing a molecular 22 19 3 4 weight of 389.41. It is a crystalline solid. It is practically insoluble in water and very slightly soluble in ethanol.

PHARMACOLOGY:

Pharmacodynamic Actions:

Mechanism of action

Tadalafil is a 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 and PDE4, enzymes which are found in the heart, brain, blood vessels, liver 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 >10,000-fold more potent for PDE5 than for PDE7 through PDE10.

Pharmacokinetic Actions:

Absorption:

Tadalafil is readily absorbed after oral administration and the mean maximum observed plasma concentration (C ) is achieved at a median time of max 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 liters, 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 appearedin the semen of healthy subjects.

Metabolism:

Tadalafil is predominantly metabolized 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 halflife 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). Tadalafil pharmacokinetics in healthy subjects is linear with respect to time and dose. Over a dose range of 2.5 mg 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 is similar to

Pharmacokinetics in subjects without erectile dysfunction.

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 clinical pharmacology studies using single dose Tadalafil (5 mg-20 mg), Tadalafil exposure (AUC) approximately doubled in subjects with mild (creatinine clearance 51 to 80 ml/min) or moderate (creatinine clearance 31 to 50 ml/min) renal impairment and in subjects with end-stage renal disease on dialysis. In hemodialysis patients, C was 41% higher than that observed in max healthy subjects. Hemodialysis contributes negligibly to Tadalafil elimination. 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 when a dose of 10 mg is administered. There is limited clinical data on the safety of Tadalafil in patients with severe hepatic insufficiency (Child-Pugh class C). If Tadalafil is prescribed, a careful individual benefit/risk evaluation should be undertaken by the prescribing physician. There are no available data about the administration of doses higher than 10 mg of Tadalafil to patients with hepatic impairment. There are no available data about the administration of once-a-day dosing of tadalafil to patients with hepatic impairment. If Tadalafil is prescribed once-a-day, a careful individual benefit/risk evaluation should be undertaken by the prescribing physician.

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.

INDICATIONS AND USAGE:

Tadalafil Tablets are indicated in the treatment of erectile dysfunction in adult males. In order for Tadalafil Tablets to be effective, sexual stimulation is required. Tadalafil Tablets are not inicated for use by women.

DOSAGE AND ADMINISTRATION:

Use in Adult Men:

In general, the recommended dose is 10 mg taken prior to anticipated sexual activity with or without food. In those patients in whom Tadalafil Tablets 10 mg does not produce an adequate effect, 20 mg might be tried. It may be taken at least 30 minutes prior to sexual activity.

The maximum dose frequency is once per day. Tadalafil Tablets 10 mg and 20 mg are intended for use prior to anticipated sexual activity and it is not recommended for continuous daily use. In patients who anticipate a frequent use of Tadalafil Tablets (i.e., at least twice weekly) a once daily regimen with the lowest doses of Tadalafil Tablets might be considered suitable, based on patient choice and the physician’s judgment. In these patients, the recommended dose is 5 mg taken once a day at approximately the same time of day. The dose may be decreased to 2.5 mg once a day based on individual tolerability. The appropriateness of continued use of the daily regimen should be reassessed periodically.

Use in Elderly Men:

Dose adjustments are not required in elderly patients. Use in Men with Impaired Renal Function: Dose adjustments are not required in patients with mild renal impairment.

For men with moderate (creatinine clearance 31 to 50 ml/min) renal impairment a starting dose of 5 mg not more than once per day is recommended and the maximum dose should be limited to 10 mg not more than once in every 48 hours. For patients with severe renal impairment, 10 mg is the maximum recommended dose. Once-a-day dosing of Tadalafil Tablets are not recommended in patients with severe renal impairment.

Use in Men with Impaired Hepatic Function:

The recommended dose of Tadalafil

Tablets are 10 mg taken prior to anticipated sexual activity with or without food.

There is limited clinical data on the safety of Tadalafil Tablets in patients with severe hepatic impairment (Child-Pugh class C); if prescribed, a careful individual benefit/risk evaluation should be undertaken by the prescribing physician. There are no available data about the administration of doses higher than 10 mg of Tadalafil to patients with hepatic impairment. Once-a-day dosing has not been evaluated in patients with hepatic impairment; therefore ifprescribed, a careful individual benefit/risk evaluation should be undertaken by the prescribing physician.

Use in Men with Diabetes:

Dose adjustments are not required in diabetic patients.

Paediatric population: Tadalafil Tablets should not be used in individuals below 18 years of age.

CONTRAINDICATIONS:

Hypersensitivity to the active substance or to any of the excipients. 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 Tablets to patients who are using any form of organic nitrate is contraindicated. Agents for the treatment of erectile dysfunction, including Tadalafil Tablets, must 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 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 mmHg), or uncontrolled hypertension.

• Patients with a stroke within the last 6 months.

Tadalafil Tablets are contraindicated in patients who have loss of vision in one eye because of non-arteritic anterior ischemic optic neuropathy (NAION), regardless of whether this episode was in connection or not with previous PDE5 inhibitor exposure.

SPECIAL WARNINGS & PRECAUTIONS:

A medical history and physical examination should be undertaken to diagnose erectile dysfunction and determine potential underlying causes, before pharmacological treatment is considered. 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 effect of nitrates.

In patients receiving concomitant antihypertensive medicines, Tadalafil may induce a blood pressure decrease. When initiating daily treatment with Tadalafil, appropriate clinical considerations should be given to a possible dose adjustment of the antihypertensive therapy. Serious cardiovascular events, including myocardial infarction, sudden cardiac death, unstable angina pectoris, ventricular arrhythmia, stroke, transient ischemic attacks, chest pain, palpitations and tachycardia, have been reported either post-marketing and/or in clinical trials.

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. Visual defects and cases of NAION have been reported in connection with the intake of Tadalafil and other PDE5 inhibitors. The patient should be advised that in case of sudden visual defect, he should stop taking Tadalafil and consult a physician immediately. Due to increased Tadalafil exposure (AUC), limited clinical experience and the lack of ability to influence clearance by dialysis, once-a-day dosing of Tadalafil is not recommended in patients with severe renal impairment.

There is limited clinical data on the safety of single-dose administration of Tadalafil in patients with severe hepatic insufficiency (Child-Pugh class C). Once-a-day administration has not been evaluated in patients with hepatic insufficiency. If Tadalafil is prescribed, a careful individual benefit/risk evaluation should be undertaken by the prescribing physician. 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. Agents for the treatment of erectile dysfunction, including Tadalafil, should be used with caution in patients with anatomical deformation of the penis (such as angulation, cavernosal fibrosis or Peyronie’s disease) or in patients who have conditions which may predispose them to priapism (such as sickle cell anaemia, multiple myeloma or leukemia). 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 who have undergone pelvic surgery or radical non-nervesparing prostatectomy.

In patients who are taking alpha1-blockers concomitant administration of Tadalafil may lead to symptomatic hypotension in some patient. The combination of Tadalafil and doxazosin is not recommended. Caution should be exercised when prescribing Tadalafil to patients using potent CYP3A4 inhibitors (Ritonavir, Saquinavir, Ketoconazole, Itraconazole, and Erythromycin), as increased Tadalafil exposure (AUC) has been observed if the medicines are combined.

The safety and efficacy of combinations of Tadalafil and other PDE5 inhibitors or other treatments for erectile dysfunction have not been studied. The patients should be informed not to take Tadalafil with such combinations. Tadalafil contains lactose monohydrate. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.

DRUG INTERACTIONS:

Interaction studies were conducted with 10 mg and/or 20 mg Tadalafil, as indicated below. With regard to those interaction studies where only the 10 mg Tadalafil dose was used, clinically relevant interactions at higher doses cannot be completely ruled out.

Effects of Other Substances on Tadalafil Tadalafil is principally metabolized by CYP3A4. A selective inhibitor of CYP3A4, Ketoconazole (200 mg daily), increased Tadalafil (10 mg) exposure (AUC) 2- fold and C by 15%, relative to the AUC and C values for Tadalafil alone. max max Ketoconazole (400 mg daily) increased Tadalafil (20 mg) exposure (AUC) 4-fold and C by 22%. Ritonavir, a protease inhibitor (200 mg twice daily), which is an max inhibitor of CYP3A4, CYP2C9, CYP2C19, and CYP2D6, increased Tadalafil (20 mg) exposure (AUC) 2-fold with no change in C . Although specific max interactions have not been studied, other protease inhibitors, such as Saquinavir, and other CYP3A4 Inhibitors, such as Erythromycin, Clarithromycin, Itraconazole, and Grapefruit juice, should be co-administered with caution, as they would be expected to increase plasma concentrations of Tadalafil. The role of transporters (for example, p-glycoprotein) in the disposition of Tadalafil is not known. There is thus the potential of drug interactions mediated by inhibition of transporters.

A CYP3A4 inducer, Rifampicin, reduced Tadalafil AUC by 88%, relative to the AUC values for Tadalafil alone (10 mg). This reduced exposure can be anticipated to decrease the efficacy of Tadalafil; the magnitude of decreased efficacy is unknown. Other inducers of CYP3A4, such as Phenobarbital, Phenytoin and Carbamazepine, may also decrease plasma concentrations of

Effects of Tadalafil on Other Medicinal Products

In clinical studies, Tadalafil (5 mg, 10 mg and 20 mg) 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. Based on the results of a clinical study in which 150 subjects received daily doses of Tadalafil 20 mg for 7 days and 0.4 mg sublingual nitroglycerin at various times, this interaction lasted for more than 24 hours and was no longer detectable when 48 hours had elapsed after the last Tadalafil dose. Thus, in a patient prescribed any dose of Tadalafil (2.5 mg – 20 mg), where nitrate administration is deemed medically necessary in a life-threatening situation, at least 48 hours should have elapsed after the last dose of Tadalafil before nitrate administration is considered. In such circumstances, nitrates should only be administered under close medical supervision with appropriate hemodynamic monitoring.

The co-administration of doxazosin (4 mg and 8 mg daily) and Tadalafil (5 mg daily dose and 20 mg as a single dose) increases the blood pressure-lowering effect of this alpha-blocker in a significant manner. This effect lasts at least twelve hours and may be symptomatic, including syncope. Therefore this combination is not recommended. In interaction studies performed in a limited number of healthy volunteers, these effects were not reported with Alfuzosin or Tamsulosin. However, caution should be exercised when using Tadalafil in patients treated with any alphablockers and notably in the elderly. Treatments should be initiated at minimal dosage and progressively adjusted. 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), betaadrenergic receptor blockers (Metoprolol), 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 (10 mg, except for studies with angiotensin II receptor blockers and Amlodipine in which a 20 mg dose was applied) had no clinically significant interaction with any of these classes. In another clinical pharmacology study, Tadalafil (20 mg) was studied in combination with up to 4 classes of antihypertensives. In subjects taking multiple antihypertensives, the ambulatory-blood-pressure changes appeared to relate to the degree of blood pressure control. In this regard, study subjects whose blood pressure was well controlled, the reduction was minimal and similar to that seen in healthy subjects. In study subjects whose blood pressure was not controlled, the reduction was greater, although this reduction was not associated with hypotensive symptoms in the majority of subjects. In patients receiving concomitant antihypertensive medicines, Tadalafil 20 mg may induce a blood pressure decrease, which (with the exception of alpha-blockers – see above) is, in general, minor and not likely to be clinically relevant. Analysis of Phase 3 clinical trial data showed no difference in adverse events in patients taking Tadalafil with or without antihypertensive medicines. However, appropriate clinical advice should be given to patients regarding a possible decrease in blood pressure when they are treated with antihypertensive medicines. When Tadalafil 10 mg was administered with Theophylline (a non-selective phosphodiesterase inhibitor) in a clinical pharmacology study, there was no pharmacokinetic interaction. The only pharmacodynamic effect was a small (3.5 bpm) increase in heart rate. Although this effect is minor and was of no clinical significance in this study, it should be considered while coadministering these medicines.

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. Alcohol concentrations (mean maximum blood concentration 0.08%) were not affected by co-administration with Tadalafil (10 mg or 20 mg). In addition, no changes in Tadalafil concentrations were seen 3 hours after co-administration with alcohol. Alcohol was administered in a manner to maximize the rate of alcohol absorption (overnight fast with no food until 2 hours after alcohol).Tadalafil (20 mg) did not augment the mean blood pressure decrease produced by alcohol (0.7g/kg or approximately 180 ml of 40% alcohol [vodka] in an 80 kg male) but, in some subjects, postural dizziness and orthostatic hypotension was observed. When Tadalafil was administered with lower doses of alcohol (0.6g/kg), hypotension was not observed and dizziness occurred with similar frequency to alcohol alone. The effect of alcohol on cognitive function was not augmented by Tadalafil (10 mg).

Tadalafil is not expected to cause clinically significant inhibition or induction of the clearance of medicinal products metabolized by CYP450 isoforms. Studies have confirmed that tadalafil does not inhibit or induce CYP450 isoforms, including CYP3A4, CYP1A2, CYP2D6, CYP2E1, CYP2C9 and CYP2C19. Tadalafil (10 mg and 20 mg) 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 (10 mg and 20 mg) did not potentiate the increase in bleeding time caused by acetylsalicylic acid. Specific interaction studies with anti-diabetic agents were not conducted.

PREGNANCY AND LACTATION:

Tadalafil Tablets are not indicated for use by women. There are limited data from the use of Tadalafil in pregnant women. Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryonic/foetal development, par turition or postnatal development. As a precautionary measure, it is preferable to avoid the use of Tadalafil during pregnancy. Tadalafil should not be used during breast feeding.\Available pharmacodynamic/toxicological data in animals have shown excretion of Tadalafil in milk. A risk to the suckling child cannot be excluded.

EFFECT TO DRIVE & USE THE MACHINE:

No studies of the effect on the ability to drive and use machines have been performed. 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 should not be used before driving or operating machinery.

ADVERSE REACTIONS:

The most commonly reported adverse reactions were headache and dyspepsia. The adverse reactions reported were transient and generally mild or moderate. Adverse reaction data are limited in patients over 75 years of age. Description of selected adverse reactions: A slightly higher incidence of ECG abnormalities, primarily sinus bradycardia, has been reported in patients treated with Tadalafil once a day as compared with placebo. Most of these ECG abnormalities were not associated with adverse reactions.

Very common (1/10), Common (1/100 to <1/10), Uncommon (1/1000 to <1/100), Rare (1/10,000 to<1/1000), Very Rare (<1/10,000) and Not known (events not reported in registration trials cannot be estimated from postmarketing spontaneous reports).

Very common: Headache

Common: Dizziness, flushing, nasal congestion, back pain and myalgia

Uncommon: Hypersensitivity reactions, blurred vision, sensations described as eye pain, dyspepsia, Cardiac disorders: Tachycardia, palpitations, hypotension (more commonly reported when tadalafil is given to patients who are already taking antihypertensive agents), hypertension, abdominal pain, gastrooesophageal reflux, rash, hyperhydrosis and chest pain.

Rare: Stroke (including hemorrhagic events), syncope, transient ischemic attacks, migraine, seizures, transient amnesia, visual field defect, swelling of eyelids, conjunctival hyperemia, non-ar teritic anterior ischemic optic neuropathy (NAION), retinal vascular occlusion, sudden hearing loss, myocardial infarction, unstable angina pectoris, ventricular arrhythmia, epistaxis, urticaria, stevens-johnson syndrome, exfoliative dermatitis prolonged erections, priapism, facial oedema, sudden cardiac death.

1 Most of the patients in whom these events have been reported had preexisting cardiovascular risk factors.

2 Sudden decrease or loss of hearing has been reported in a small number of post-marketing and clinical trial cases with the use of all PDE5 inhibitors, including Tadalafil.

3 Postmarketing surveillance reported adverse reactions not observed in placebo-controlled clinical trials.

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.

PACKING:

Blister of 10 Tablets/Blister of 4 Tablets.

STORAGE: Store in a dry place below 30 C. Protect from light.

Keep out of reach of Children.