Amotad 5mg & 20mg Tablets

AMOTAD is indicated only for the treatment of erectile dysfunction in adult males. Sexual stimulation is required for AMOTAD to be effective.

Posology
Use in adult men: The recommended dose is 5 mg taken once a day at approximately the same time of day. The recommended maximum dose of AMOTAD 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 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 is once per day.

Special populations
Men with renal impairment: Dose adjustments are not required in patients with mild to moderate renal impairment. For patients with severe renal impairment, once a day dosing of AMOTAD is not recommended.

Method of administration
For oral use

Hypersensitivity to tadalafil or to any of the excipients listed in section 6.1. 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 (See section 4.5).

Patients with severe hepatic insufficiency (Child-Pugh Class C) Tadalafil must not be used in men with cardiac disease for whom sexual activity is inadvisable. Medical practitioners 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 dysrhythmias, hypotension (< 90/50mmHg), or uncontrolled hypertension,
• patients with a stroke within the last 6 months.

Tadalafil is contraindicated in patients who have loss of vision in one eye because of 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 vestibular symptoms. 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 (see section 4.5).

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, medical practitioners 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 (see section 5.1), and as such potentiates the hypotensive effect of nitrates (see section 4.3).

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 Serious cardiovascular events, including myocardial infarction, sudden cardiac death, unstable angina pectoris, ventricular dysrhythmia, 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, 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. Medical practitioners 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 (see section 4.5). 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 AMOTAD and consult a medical practitioner immediately (see section 4.3).

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 and previous hearing loss history) patients should be advised to stop taking AMOTAD and 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, 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).

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. AMOTAD 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 inducers or inhibitors 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 medicinal products are combined (see section 4.5).

Tadalafil and other 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. The patients should be informed not to take Tadalafil in such combinations.

Lactose AMOTAD contains lactose. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.

Effects of other medicinal products on tadalafil Cytochrome P450 inhibitors Tadalafil 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) exposure (AUC) 4-fold and C max by 22 %. Ritonavir, a protease inhibitor (200 mg twice daily), which is an inhibitor of CYP3A4, CYP2C9, CYP2C19, and CYP2D6, increased tadalafil (20 mg) exposure (AUC) 2-fold with no change in C max . Although specific 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 (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.

P-glycoprotein substrates (e.g. digoxin) Tadalafil (40 mg once per day) had no clinically significant effect on the pharmacokinetics of digoxin.

Cytochrome P450 inducers 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 phenobarbitone, phenytoin, and carbamazepine, may also decrease plasma concentrations of tadalafil.

Effects of tadalafil on other medicinal products Nitrates 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 (see section 4.3). 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 to 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 haemodynamic monitoring.

Anti-hypertensives (including calcium channel blockers) 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 12 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. However caution should be exercised when using tadalafil in patients treated with any alpha-blockers, 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 medicinal products was examined. Major classes of antihypertensive medicinal products were studied, 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. 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 medicinal products, tadalafil 20 mg may induce a blood pressure decrease, which (with the exception of alpha-blockers -doxazosin 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 medicinal products. However, appropriate clinical advice should be given to patients regarding a possible decrease in blood pressure when they are treated with antihypertensive medicinal products.

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 favourable clinical effect of the combination in the population studied. Concomitant use of riociguat with PDE5 inhibitors, including tadalafil, is contraindicated (see section 4.3).

5-alpha reductase inhibitors In a clinical trial that compared tadalafil 5 mg co-administered with finasteride 5 mg to placebo plus finasteride 5 mg in the relief of benign prostatic hyperplasia symptoms, no new adverse reactions were identified. However, as a formal medicine 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.

CYP1A2 substrates (e.g. theophylline) 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 when co-administering these medicinal products.

Oral contraceptive pill At steady-state, tadalafil (40 mg once per day) increased ethinylestradiol exposure (AUC) by 26 % and Cmax 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 Cmax 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.

Alcohol 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 maximise 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 (0.7 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. 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).

AMOTAD is not indicated for use by women

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/foetal development, parturition or postnatal development (see section 5.3). As a precautionary measure, it is preferable to avoid the use of Tadalafil during pregnancy.

Breast-feeding Available pharmacodynamic/toxicological data in animals have shown excretion of tadalafil in milk. A risk to the suckling 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 (see sections 5.1 and 5.3).

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 AMOTAD , 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 summary of adverse reactions The table below lists the adverse reactions observed from spontaneous reporting and in placebo-controlled clinical trials for on-demand and once-a-day treatment of erectile dysfunction

Very common Frequent Less frequent Frequency unknown

Immune system disorders Hypersensitivity reactions Angioedema

Nervous system disorders Headache Dizziness Stroke (including haemorrhagic events), Syncope, Transient ischaemic attacks, Migraine, Seizures, Transient amnesia

Eye disorders Blurred vision, Sensations described as eye pain Visual field defect, Swelling of eyelids, Conjunctival hyperaemia, Non-arteritic anterior ischaemic optic neuropathy (NAION), Retinal vascular occlusion, Retinal detachment.

Ear and labyrinth disorders Tinnitus Sudden hearing loss

Cardiac disorders 1 Tachycardia, Palpitations Myocardial infarction, Unstable angina pectoris, Ventricular dysrhythmia

Vascular disorders Flushing Hypotension, Hypertension

Respiratory, thoracic and mediastinal disorders Nasal congestion Dyspnoea, Epistaxis

Gastrointestinal disorders Dyspepsia Abdominal pain, Vomiting, Nausea, Gastro- oesophageal reflux

Skin and subcutaneous tissue disorders Rash Urticaria, Stevens-Johnson syndrome, Exfoliative dermatitis, Hyperhydrosis (sweating)

Musculoskeletal, connective tissue and bone disorders Back pain, Myalgia, Pain in extremity

Renal and urinary disorders Haematuria

Reproductive system and breast disorders Prolonged erections Priapism, Penile haemorrhage, Haematospermia

General disorders and administration site conditions Chest pain , Peripheral oedema, Fatigue Facial oedema, Sudden cardiac death

Reporting of suspected adverse reactions Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions to SAHPRA via the u201c6.04 Adverse Drug Reaction Reporting Formu201d , found online under SAHPRAu2019s publications: https://www.sahpra.org.za/Publications/Index/8

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. Haemodialysis contributes negligibly to tadalafil elimination.