TADAGRA

The active ingredient of TADAGRA is Tadalafil. Urological drugs used in erectile dysfunction.

PRESENTATION

Each film-coated tablet contains 5/10 mg Tadalafil.

PHARMACOLOGICAL PROPERTIES

Pharmacotherapeutic Group: Urological, drugs used in erectile dysfunction.

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 treatment of erectile dysfunction in the absence of sexual stimulation.

As Tadalafil is a potent and selective inhibitor of phosphodiesterase type 5 (PDE5), the enzyme responsible for the degradation of cyclic guanosine monophosphate (cGMP). Pulmonary arterial hypertension is associated with impaired release of nitric oxide by the vascular endothelium and consequent reduction of cGMP concentrations within the pulmonary vascular smooth muscle. PDE5 is the predominant phosphodiesterase in the pulmonary vasculature. Inhibition of PDE5 by Tadalafil increases the concentrations of cGMP resulting in relaxation of the pulmonary vascular smooth muscle cell and vasodilation of the pulmonary vascular bed.

Pharmacodynamics Effects

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 photo transduction. Tadalafil is also > 10,000-fold more potent for PDE5 than for PDE7 through PDE10.

PHARMACOKINETIC PROPERTIES

Absorption

Tadalafil is readily absorbed after oral administration and the mean maximum observed plasma concentration (C_max) is achieved at a median time of 4 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 after a single 10 mg administration) had no clinically relevant effects on the rate and extent of absorption.

Distribution

The mean volume of distribution is approximately 77 l at steady state, 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 metabolized by the cytochrome P450 (CYP) 3A4 isoform. The major circulating metabolite is the methyl catechol 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 3.4 l/h at steady state and the mean terminal half-life is 16 hours in healthy subjects. Tadalafil is excreted predominantly as inactive metabolites, mainly in the faces (approximately 61 % of the dose) and to a lesser extent in the urine (approximately 36 % of the dose).

INTERACTION WITH OTHER MEDICINAL PRODUCTS AND OTHER FORMS OF INTERACTION

Effects of other substances on Tadalafil

• Cytochrome P450 Inhibitors
• Azole Antifungals (e.g. ketoconazole)

Ketoconazole (200 mg daily), increased Tadalafil (10 mg) single-dose exposure (AUC) 2-fold and C_max by 15%, relative to the AUC and C_max values for Tadalafil alone. Ketoconazole (400 mg daily) increased Tadalafil (20 mg) single-dose exposure (AUC) 4-fold and C_max by 22%.

• Protease inhibitors (e.g. ritonavir)

Ritonavir (200 mg twice daily), which is an inhibitor of CYP3A4, CYP2C9, CYP2C19, and CYP2D6, increased Tadalafil (20 mg) single-dose exposure (AUC) 2-fold with no change in C_max. Ritonavir (500 mg or 600 mg twice daily) increased Tadalafil (20 mg) single-dose exposure (AUC) by 32% and decreased C_max by 30%.

Cytochrome P450 Inducers

• Endothelin-1 receptor antagonists

A substrate of CYP2C9 and CYP3A4 and a moderate inducer of CYP3A4, CYP2C9 and possibly CYP2C19, reduced Tadalafil (40 mg once per day) systemic exposure by 42% and C_max by 27% following multiple dose co-administration. The efficacy of Tadalafil in patients already on bosentan therapy has not been conclusively demonstrated. Tadalafil did not affect the exposure (AUC and C_max) of bosentan or its metabolites.

The safety and efficacy of combinations of Tadalafil and other endothelin-1 receptor antagonists have not been studied.

• Antimicrobial medicinal products (e.g. rifampicin)

A CYP3A4 inducer, rifampicin (600 mg daily), reduced Tadalafil AUC by 88% and C_max by 46%, relative to the AUC and C_max values for Tadalafil alone (10 mg).

Effects of Tadalafil on other medicinal products

• Nitrates

In clinical studies, Tadalafil (5, 10 and 20 mg) was shown to augment the hypotensive effects of nitrates. This interaction lasted for more than 24 hours and was no longer detectable when 48 hours had elapsed after the last Tadalafil dose. Therefore, administration of Tadalafil to patients who are using any form of organic nitrate is contraindicated (see section 4.3).

• Anti-hypertensive (including Calcium channel blockers)

The co-administration of Doxazosin (4 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 (see section 4.4).

In interaction studies performed in a limited number of healthy volunteers, these effects were not reported with Alfuzosin or Tamsulosin.

In clinical pharmacology studies, the potential for Tadalafil (10 and 20 mg) to augment the hypotensive effects of antihypertensive medicinal products was examined. Major classes of antihypertensive medicinal products were studied either as monotherapy or as part of combination therapy. In patients taking multiple antihypertensive medicinal products whose hypertension was not well controlled, greater reductions in blood pressure were observed compared to patients whose blood pressure was well controlled, where the reduction was minimal and similar to that in healthy subjects. In patients receiving concomitant antihypertensive medicinal products, Tadalafil 20 mg may induce a blood pressure decrease, which (with the exception of Doxazosin - see above) is, in general, minor and not likely to be clinically relevant.

• Riociguat

Preclinical studies showed an additive systemic blood pressure lowering effect when PDE5 inhibitors were combined with riociguat. In clinical studies, riociguat has been shown to augment the hypotensive effects of PDE5 inhibitors. There was no evidence of favorable clinical effect of the combination in the population studied. Concomitant use of riociguat with PDE5 inhibitors, including Tadalafil, is contraindicated.

• Alcohol

Alcohol concentrations were not affected by co-administration with Tadalafil (10 mg or 20 mg). In addition, no changes in Tadalafil concentrations were seen after co-administration with alcohol. Tadalafil (20 mg) did not augment the mean blood pressure decrease produced by alcohol (0.7 g/kg or approximately 180 ml of 40% alcohol [vodka] in an 80 kg male), but in some subjects, postural dizziness and orthostatic hypotension were observed. The effect of alcohol on cognitive function was not augmented by Tadalafil (10 mg).

• CYP1A2 substrates (e.g. theophylline)

When Tadalafil 10 mg was administered with theophylline (a non-selective phosphodiesterase inhibitor) there was no pharmacokinetic interaction. The only pharmacodynamics effect was a small (3.5 bpm) increase in heart rate.

• CYP2C9 substrates (e.g. R-warfarin)

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.

• Acetylsalicylic acid

Tadalafil (10 mg and 20 mg) did not potentiate the increase in bleeding time caused by acetyl salicylic acid.

• P-glycoprotein substrates (e.g. digoxin)

Tadalafil (40 mg once per day) had no clinically significant effect on the pharmacokinetics of digoxin.

• Oral contraceptive pill

At steady-state, Tadalafil (40 mg once per day) increased Ethinylestradiol exposure (AUC) by 26% and C_max by 70% relative to oral contraceptive administered with placebo. There was no statistically significant effect of Tadalafil on Levonorgestrel which suggests the effect of ethinylestradiol is due to inhibition of gut sulphation by Tadalafil. The clinical relevance of this finding is uncertain.

• Terbutaline

A similar increase in AUC and C_max seen with ethinylestradiol may be expected with oral administration of Terbutaline, probably due to inhibition of gut Sulphation by Tadalafil. The clinical relevance of this finding is uncertain.

CLINICAL PARTICULARS

Therapeutic Indications

• Treatment of erectile dysfunction in adult males.
• In order for Tadalafil to be effective for the treatment of erectile dysfunction, sexual stimulation is required.
• Tadalafil 10 mg is not indicated for use by women.

• It is indicated in adults for the treatment of pulmonary arterial hypertension (PAH) classified as WHO functional class II and III, to improve exercise capacity
• Efficacy has been shown in idiopathic PAH (IPAH) and in PAH related to collagen vascular disease.

Posology and Method of Administration

Posology

Adult Men

• In general, the recommended dose is 10 mg taken prior to anticipated sexual activity and with or without food.
• In those patients in whom Tadalafil 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 10 mg and 20 mg is intended for use prior to anticipate sexual activity and it is not recommended for continuous daily use.

Pulmonary arterial hypertension

• Treatment should only be initiated and monitored by a physician experienced in the treatment of PAH.

Posology

• The recommended dose is 40 mg (2 x 20 mg) taken once daily with or without food.

Special Populations

• Elderly Men

Dose adjustments are not required in elderly patients.

• Men with Renal Impairment

Dose adjustments are not required in patients with mild to moderate renal impairment. For patients with severe renal impairment, 10 mg is the maximum recommended dose for on-demand treatment.

Once-a-day dosing of Tadalafil is not recommended in patients with severe renal impairment.

• Men with Hepatic Impairment

For the treatment of erectile dysfunction using on-demand Tadalafil the recommended dose of Tadalafil is 10 mg taken prior to anticipated sexual activity and with or without food. Once-a-day dosing of Tadalafil for the treatment of erectile dysfunction has not been evaluated in patients with hepatic impairment; therefore if prescribed, a careful individual benefit/risk evaluation must be undertaken by the prescribing physician.

• Men with Diabetes

Dose adjustments are not required in diabetic patients.

• Pediatric population

There is no relevant use of Tadalafil in the pediatric population with regard to the treatment of erectile dysfunction.

Method of Administration

TADAGRA is for oral use.

SIDE EFFECTS/UNDESIRABLE EFFECTS

Tabulated Summary of Adverse Reactions

Frequency estimate: Very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000), very rare (<1/10,000) and not known (cannot be estimated from the available data).

 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 with erectile dysfunction. Adverse reactions 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.

SPECIAL WARNINGS AND PRECAUTIONS FOR USE

Before treatment with Tadalafil

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. 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-nerve-sparing prostatectomy.

Cardiovascular

The following groups of patients with cardiovascular disease were not included in PAH clinical studies:

• • Patients with clinically significant aortic and mitral valve disease
  • Patients with pericardial constriction
  • Patients with restrictive or congestive cardiomyopathy
  • Patients with significant left ventricular dysfunction
  • Patients with life-threatening arrhythmias
  • Patients with symptomatic coronary artery disease
  • Patients with uncontrolled hypertension.
• Since there are no clinical data on the safety of tadalafil in these patients, the use of tadalafil is not recommended.
• Pulmonary vasodilators may significantly worsen the cardiovascular status of patients with pulmonary veno-occlusive disease (PVOD). Since there are no clinical data on administration of tadalafil to patients with veno-occlusive disease, administration of tadalafil to such patients is not recommended. Should signs of pulmonary edema occur when tadalafil is administered, the possibility of associated PVOD should be considered.
• Tadalafil has systemic vasodilatory properties that may result in transient decreases in blood pressure. Physicians should carefully consider whether their patients with certain underlying conditions, such as severe left ventricular outflow obstruction, fluid depletion, autonomic hypotension or patients with resting hypotension, could be adversely affected by such vasodilatory effects.
• In patients who are taking alpha₁ blockers concomitant administration of tadalafil may lead to symptomatic hypotension in some patients. Therefore, the combination of tadalafil and doxazosin is not recommended.

Vision

Visual defects and cases of NAION have been reported in connection with the intake of tadalafil and other PDE5 inhibitors. Analyses of observational data suggest an increased risk of acute NAION in men with erectile dysfunction following exposure to tadalafil or other PDE5 inhibitors. As this may be relevant for all patients exposed to tadalafil, the patient should be advised that in case of sudden visual defect, he should stop taking TADAGRA and consult a physician immediately. Patients with known hereditary degenerative retinal disorders, including retinitis pigmentosa, were not included in the clinical studies, and use in these patients is not recommended.

Decreased or sudden hearing loss

Cases of sudden hearing loss have been reported after the use of tadalafil. Although other risk factors were present in some cases (such as age, diabetes, hypertension, previous hearing loss history and associated connective tissue diseases) patients should be advised to seek prompt medical attention in the event of sudden decrease or loss of hearing.

Renal and hepatic impairment

Due to increased tadalafil exposure (AUC), limited clinical experience, and the lack of ability to influence clearance by dialysis, tadalafil is not recommended in patients with severe renal impairment.

Patients with severe hepatic cirrhosis (Child-Pugh Class C) have not been studied and, therefore, dosing of tadalafil is not recommended.

Priapism and anatomical deformation of the penis

Priapism has been reported in men treated with PDE5 inhibitors. 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 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 anemia, multiple myeloma or leukemia).

Use with CYP3A4 inducers or inhibitors

For patients chronically taking potent inducers of CYP3A4, such as rifampicin, the use of tadalafil is not recommended.

For patients taking concomitant potent inhibitors of CYP3A4, such as ketoconazole or ritonavir, the use of tadalafil is not recommended.

Treatments for erectile dysfunction

The safety and efficacy of combinations of tadalafil and other PDE5 inhibitors or other treatments for erectile dysfunction have not been studied. Patients should be informed not to take tadalafil with these medicinal products.

Prostacyclin and its analogues

The efficacy and safety of Tadalafil co-administered with prostacyclin or its analogues has not been studied in controlled clinical studies. Therefore, caution is recommended in case of co-administration.

FERTILITY, PREGNANCY AND LACTATION

Pregnancy

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, Embryonal/fetal development, parturition or postnatal development. As a precautionary measure, it is preferable to avoid the use of Tadalafil during pregnancy.

Breast feeding

Available pharmacodynamics/toxicological data in animals have shown excretion of Tadalafil in milk. A risk to the breastfed child cannot be excluded. Tadalafil should not be used during breast feeding.

Fertility

Effects were seen in dogs that might indicate impairment of fertility. Two subsequent clinical studies suggest that this effect is unlikely in humans, although a decrease in sperm concentration was seen in some men.

Effects on Ability to Drive and Use Machines

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 studies was similar, patients should be aware of how they react to Tadalafil, before driving or operating machinery.

CONTRAINDICATIONS

• Hypersensitivity to the active substance or to any of the excipients
• Acute myocardial infarction within the last 90 days.
• Severe hypotension (<90/50 mm Hg).

• 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.
• The co-administration of PDE5 inhibitors, including Tadalafil, with guanylate cyclase stimulators, such as riociguat, is contraindicated as it may potentially lead to symptomatic hypotension.
• 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 .