Tadalafil Dyna 5 mg & 20 mg FC tablets.

TADALAFIL DYNA is indicated for the treatment of erectile dysfunction. In order for TADALAFIL DYNA to be effective, sexual stimulation is required.

Posology
In adult men: The recommended dose 5 mg taken once a day at approximately the same time of day. The recommended maximum dose of TADALAFIL DYNA is 20 mg taken prior to anticipated sexual activity and without regard to food. TADALAFIL DYNA can be taken up to 36 hours and as early as 16 minutes prior to sexual activity. Patients may initiate sexual activity at varying time points relative to dosing in order to determine their own optimal window of responsiveness. The maximum recommended dosing frequency of TADALAFIL DYNA is once per day.

Special populations
Renal impairment
Dosage adjustments are not required in patients with mild or moderate renal impairment. Once-a-day dosing of TADALAFIL DYNA is not recommended in patients with severe renal impairment.

Paediatric population
TADALAFIL DYNA is not indicated for children under the age of 18 years.

Method of administration
For oral use.

• hypersensitivity to tadalafil or to any of the ingredients of TADALAFIL DYNA (see section 6.1)
• administration of TADALAFIL DYNA to patients who are using any form of organic nitrate
• patients with severe hepatic insufficiency (Child-Pugh Class C)
• loss of vision in one or both eyes because on non-arteritic anterior ischaemic optic neuropathy (NAION) regardless of whether this episode was in connection or not with previous PDE5 inhibitor exposure (see section 4.4)
• previous experience of unilateral or bilateral decrease or loss of hearing with or without associated vesicular symptoms.
• 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 dysrhythmias, hypotension (< 90/50 mm Hg), or uncontrolled hypertension
• patients with a stroke within the last 6 months
• concomitant therapy with guanylate cyclase stimulators, such as riociguat due to the possibility of symptomatic hypotension (see section 4.5).

Before treatment with TADALAFIL DYNA: A medical history and physical examination should be undertaken to diagnose erectile dysfunction determine potential underlying causes, before pharmacological treatment is considered. Sexual activity carries a potential cardiac risk for patients with pre-existing cardiovascular disease. Prior to initiating any treatment for erectile dysfunction, medical practitioners should consider the cardiovascular status of their patients. Tadalafil has vasodilator properties, resulting in mild and transient decreases in blood pressure (see section 5.1) and as such potentiates the hypotensive effect of nitrates (see section 4.3). TADALAFIL DYNA should not be used in men with cardiac disease for whom sexual activity is inadvisable.

It is not known if tadalafil is effective in patients who have undergone pelvic surgery or radical non-nerve-sparing prostatectomy.

Cardiovascular: Serious cardiovascular events, including myocardial infarction, sudden cardiac death, unstable angina pectoris, ventricular arrhythmia, stroke, transient ischaemic 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 DYNA, to sexual activity, or to a combination of these or other factors.

Tadalafil has systemic vasodilatory properties that may result in transient decreases in blood pressure. Prior to prescribing TADALAFIL DYNA, physicians should carefully consider whether their patients with underlying cardiovascular disease could be affected adversely by such vasodilatory effects.

- In patients receiving concomitant antihypertensive medicinal products, 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.

In patients who are taking alpha-1 blockers, such as prazosin and doxazosin, concomitant administration of TADALAFIL DYNA may lead to systematic hypotension in some patients (see section 4.5). The combination of tadalafil and doxazosin is not recommended as an augmentation of the blood-pressure-lowering effect of doxazosin was observed during concomitant administration (4 to 8 mg doxazosin daily) in healthy subjects. In a clinical pharmacology study of 18 healthy volunteers who received a single dose of tadalafil no symptomatic hypotension was observed with simultaneous administration of tamsulosin, an u03b1-1 blocker (see section 4.5).

Patients who experience symptoms of cardiac disease upon initiation of sexual activity should be advised to refrain from further sexual activity and should report the episode to their medical practitioner.

Vision: Non-arteritic anterior ischaemic optic neuropathy (NAION) is a cause of decreased vision including permanent loss of vision. Visual defects and cases of NAION have been reported in connection with the intake of TADALAFIL DYNA 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 TADALAFIL DYNA and consult a medical practitioner immediately (see section 4.3). Individuals who have already experienced NAION should be advised to not use TADALAFIL DYNA or other PDE5 inhibitors again (see section 4.3).

Decreased or sudden loss of hearing: Cases of sudden hearing loss have been reported after the use of tadalafil. Patients should be advised to stop taking TADALAFIL DYNA and seek prompt medical attention in the event of sudden decrease or loss of hearing. These events may be accompanied by tinnitus and dizziness. It is not possible to determine whether these events are related directly to the use of PDE5 inhibitors or to other factors (see section 4.8).

Renal and hepatic impairment: 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. Clinical study results with tadalafil indicate that patients with moderate renal failure (creatinine clearance = 31 to 50 mL/min) was less well tolerated in terms of back pain than in patients with mild renal failure (creatinine clearance = 51 to 80 mL/min) and healthy subjects.

There is limited clinical data on the safety of single-dose administration of TADALAFIL DYNA in patients with severe hepatic insufficiency (Child-Pugh Class C). It is therefore contraindicated in patients with severe hepatic insufficiency (see section 4.3).

Priapism and anatomical deformation of the penis: 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 DYNA 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 leukaemia).

Use with CYP3A4 inhibitors: Caution should be exercised when prescribing TADALAFIL DYNA 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 (see section 4.5).

TADALAFIL DYNA and other treatments for erectile dysfunction: The safety and efficacy of combinations of TADALAFIL DYNA and other PDE5 inhibitors or other treatments for erectile dysfunction have not been studied. The patients should be informed not to take TADALAFIL DYNA in such combinations.

Lactose: Patients with the rare hereditary conditions of galactose intolerance, total lactase deficiency, glucose-galactose malabsorption should not take TADALAFIL DYNA.

Sodium: This medicine contains less than 1 mmol sodium (23 mg) per film coated tablet, 5 and 20 mg, that is to say essentially u2018sodium-freeu2019.

Effect of other medicines on tadalafil
Cytochrome P450 inhibitors TADALAFIL DYNA is principally metabolised by CYP3A4. A selective inhibitor of CYP3A4, ketoconazole (200 mg daily), increased tadalafil (10 mg) 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 %. Ritonavir (200 mg twice daily) an inhibitor of CYP3A4, 2C9, 2C19 and 2D6, increased tadalafil single-dose exposure (AUC) by 124 % with no change in C max. Although specific interactions have not been studied, other HIV 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 (see section 4.4). Consequently, the incidence of the adverse reactions listed in section 4.8 might be increased.

Transporters
The role of transporters (for example, p-glycoprotein) in the disposition of tadalafil is not known. Therefore, there is the potential of medicine interactions mediated by inhibition of transporters.

Cytochrome P450 inducers
A selective CYP3A4 inducer, rifampicin (rifampicin, 600 mg daily), reduced tadalafil single-dose exposure (AUC) by 88 % and C max by 46 %, relative to the AUC and C max values for tadalafil alone. This reduced exposure can be anticipated to decrease the efficacy of tadalafil; the magnitude of decreased efficacy is unknown. It can be expected that concomitant administration of other CYP3A4 inducers, such as phenobarbitone, phenytoin and carbamazepine may also decrease plasma concentrations of tadalafil.

Antacids
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.

H2-antagonists
An increase in gastric pH resulting from administration of nizatidine, an H 2 antagonist, had no significant effect on tadalafil pharmacokinetics.

Effects of tadalafil on other medicines
Nitrates
In clinical studies, tadalafil 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 (see section 4.3). Based on the results of a clinical study in which 150 subjects receiving 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 DYNA (5 mg or 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 DYNA before nitrate administration is considered. In such circumstances, nitrates should only be administered under close medical supervision with appropriate haemodynamic monitoring.

Anti-hypertensives (including calcium channel blockers)
Tadalafil has systemic vasodilatory properties and may augment the blood pressure lowering effects of antihypertensive medicines including calcium channel blockers (amlodipine), angiotensin converting enzyme (ACE) inhibitors (enalapril), beta-adrenergic 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. Additionally, in patients taking multiple antihypertensive medicines whose hypertension was not well controlled, greater reductions in blood pressure were observed. These reductions were not associated with hypotensive symptoms in the vast majority of patients. Appropriate clinical advice should be given to patients when they are treated with antihypertensive medications and tadalafil. Tadalafil had no clinically significant effect on blood pressure changes due to tamsulosin, an u03b1-adrenergic receptor blocking agent. 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. Some patients experienced dizziness. Therefore, this combination is not recommended (see section 4.4).

CYP1A2 substrates
Tadalafil had no clinically significant effect on the pharmacokinetics or pharmacodynamics of theophylline, a CYP1A2 substrate.

Ethinylestradiol and terbutaline
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
Tadalafil did not affect alcohol concentrations and alcohol did not affect tadalafil concentrations. At high doses of alcohol (0,7 g/kg), the addition of tadalafil did not induce statistically significant mean blood pressure decreases. In some subjects, postural dizziness and orthostatic hypotension were observed. When tadalafil was administered with lower doses of alcohol (0,6 g/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).

Cytochrome P450 metabolised medicines
Tadalafil does not inhibit or induce CYP450 isoforms, including CYP1A2, CYP3A4, CYP2C9, CYP2C19, CYP2D6 and CYP2E1.

CYP2C9 substrates (e.g. R-warfarin)
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.

Aspirin
Tadalafil did not potentiate the increase in bleeding time caused by aspirin.

Antidiabetic medicinal products
Specific interaction studies with antidiabetic medicinal products were not conducted.

Riociguat
Studies have shown an additive systemic blood pressure lowering effect when PDE5 inhibitors were combined with riociguat. Riociguat has been shown to augment the hypotensive effects of PDE5 inhibitors. There was no evidence of favourable clinical effect of the combination. Concomitant use of riociguat with PDE5 inhibitors, including tadalafil, is contraindicated (see section 4.3).

5-alpha reductase inhibitors
No new adverse reactions were identified when tadalafil was co-administered with finasteride. However, as a formal interaction study evaluating the effects of tadalafil and 5-alpha reductase inhibitors (5-ARIs) has not been performed, caution should be exercised when tadalafil is co-administered with 5-ARIs.

TADALAFIL DYNA is not indicated for use by women. Safety and efficacy of TADALAFIL DYNA in pregnancy and lactation have not been established.

Pregnancy
TADALAFIL DYNA should not be used during pregnancy.

Breastfeeding
TADALAFIL DYNA should not be used during breastfeeding.

Fertility
Although animal studies indicate impairment of fertility, subsequent clinical studies suggest this is unlikely in humans. A decrease in sperm concentration has however, been seen in some men (see section 5.3).

TADALAFIL DYNA has a negligible influence on the ability to drive or use machines. However, there have been reports of dizziness, therefore patients should be aware of how they react to TADALAFIL DYNA before driving or using machines.

Summary of the safety profile
The most commonly reported adverse reactions in patients taking tadalafil for the treatment of erectile dysfunction were headache, dyspepsia, back pain and myalgia, in which the incidences increase with increasing dose of tadalafil. The adverse reactions reported were transient, and generally mild or moderate. The majority of headaches reported with tadalafil once-a-day dosing are experienced within the first 10 to 30 days of starting treatment.

Tabulated list of adverse effects

1 Most of the patients had pre-existing cardiovascular risk factors (see Section 4.4).

2 Post marketing surveillance reported adverse reactions not observed in placebo controlled clinical trials.

3 More commonly reported when tadalafil is given to patients who are already taking antihypertensive medicinal products.

a. 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.

b. Other special populations
Although there is limited data in patients over 65 years of age, in clinical trials with tadalafil taken on demand for the treatment of erectile dysfunction, diarrhoea was reported more frequently in patients over 65 years of age. In clinical trials with tadalafil 5 mg, taken once a day for the treatment of benign prostatic hyperplasia, dizziness and diarrhoea were reported more frequently in patients over 75 years of age.

Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicine is important. It allows continued monitoring of the benefit/risk balance of the medicine. Healthcare professionals are requested to report any suspected adverse drug reactions to SAHPRA via the Med Safety APP (Medsafety X SAHPRA) and eReporting platform (who-umc.org) found on SAHPRA website. An email can be sent directly to the company, [email protected], to ensure safety of the product.

Signs and symptoms: 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.

Management of overdose: In cases of overdose, standard supportive measures should be adopted as required. Haemodialysis contributes negligibly to tadalafil elimination.