Tadalafil 10mg film-coated tablets

Aspire Pharma Ltd🇬🇧 Electronic Medicines Compendium

Approval Date: N/A
Approval ID: b7d64d50d310b463
Company: Aspire Pharma Ltd
Type: Standard

Approval Details

Approval Id: b7d64d50d310b463
Drug Approval Emc Name: Tadalafil 10mg film-coated tablets
Drug Name: Tadalafil 10mg film-coated tablets
Company Name: Aspire Pharma Ltd
Company Address: 4 Rotherbrook Court, Bedford Road, Petersfield, Hampshire, GU32 3QG, UK
Company Website: http://www.aspirepharma.co.uk
Company Telephone: +44 (0)1730 231148
Company Medical Info Direct Line: +44 (0)1730 231148
Company Customer Care Direct Line: +44 (0)1730 231148
Atc Code: G04BE08
Legal Category: Prescription only medicine
Authorisation Holder: Aspire Pharma Ltd Unit 4 Rotherbrook Court Bedford Road Petersfield Hampshire GU32 3QG United Kingdom
Authorisation Number: PL35533/0067
Authorisation Date: 17/09/2021
Instruction Authorisation Holder: Aspire Pharma Ltd Unit 4 Rotherbrook Court Bedford Road Petersfield Hampshire GU32 3QG United Kingdom
Instruction Authorisation Number: PL35533/0067
Instruction Authorisation Date: 17/09/2021
Instruction Composition: Each 10mg tablet contains 10mg tadalafil. \*\*Excipient(s) with known effect\*\* Each coated tablet contains 163.40mg of lactose (as monohydrate). For the full list of excipients, see section 6.1.
Instruction Dosage Form: Film-coated tablet. The 10mg tablets are light yellow to yellow, round shaped, film-coated tablets imprinted with '338' on one side.
Instruction Clinical Particulars: 4.1 Therapeutic indications Treatment of erectile dysfunction in adult males. In order for Tadalafil to be effective, sexual stimulation is required. Tadalafil is not indicated for use by women.4.2 Posology and method of administration \*\*Posology\*\* \*Adult men\* In general, the recommended dose is 10mg taken prior to anticipated sexual activity and with or without food. In those patients in whom Tadalafil 10mg does not produce an adequate effect, 20mg might be tried. It may be taken at least 30 minutes prior to sexual activity. The maximum dose frequency is once per day. Tadalafil 10mg and 20mg is 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 (i.e., at least twice weekly) a once daily regimen with the lowest doses of Tadalafil might be considered suitable, based on patient choice and the physician's judgement. In these patients, the recommended dose is 5mg taken once a day at approximately the same time of day. The dose may be decreased to 2.5mg once a day based on individual tolerability. The appropriateness of continued use of the daily regimen should be reassessed periodically. \*\*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, 10mg is the maximum recommended dose. Once-a-day dosing tadalafil is not recommended in patients with severe renal impairment. (See sections 4.4 and 5.2.) \*Men with Hepatic Impairment\* The recommended dose of Tadalafil is 10mg taken prior to anticipated sexual activity and with or without food. There is limited clinical data on the safety of Tadalafil 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 10mg of tadalafil to patients with hepatic impairment. Once-a-day dosing has not been evaluated in patients with hepatic impairment; therefore, if prescribed, a careful individual benefit/risk evaluation should be undertaken by the prescribing physician. (See sections 4.4 and 5.2.) \*Men with Diabetes\* Dose adjustments are not required in diabetic patients. \*Paediatric population\* There is no relevant use of Tadalafil in the paediatric population with regard to the treatment of erectile dysfunction. \*\*Method of administration\*\* For oral use.4.3 Contraindications Hypersensitivity to the active substance 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.) Tadalafil, 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 (<90/50mmHg), 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). 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).4.4 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 (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 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, to sexual activity, or to a combination of these or other factors. 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 Tadalafil and consult a physician 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 tadalafil and seek prompt medical attention in the event of sudden decrease or loss of hearing. \*\*Hepatic 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). If Tadalafil is prescribed, a careful individual benefit/risk evaluation should be undertaken by the prescribing physician. \*\*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, 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 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\*\* Tadalafil contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.4.5 Interaction with other medicinal products and other forms of interaction Interaction studies were conducted with 10mg and/or 20mg tadalafil, as indicated below. With regard to those interaction studies where only the 10mg tadalafil dose was used, clinically relevant interactions at higher doses cannot be completely ruled out. \*\*Effects of Other Substances on Tadalafil\*\* \*Cytochrome P450 inhibitors\* Tadalafil is principally metabolised by CYP3A4. A selective inhibitor of CYP3A4, ketoconazole (200mg daily), increased tadalafil (10mg) exposure (AUC) 2-fold and Cmax by 15%, relative to the AUC and Cmax values for tadalafil alone. Ketoconazole (400mg daily) increased tadalafil (20mg) exposure (AUC) 4-fold and Cmax by 22%. Ritonavir, a protease inhibitor (200mg twice daily), which is an inhibitor of CYP3A4, CYP2C9, CYP2C19, and CYP2D6, increased tadalafil (20mg) exposure (AUC) 2-fold with no change in Cmax. 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 drug interactions mediated by inhibition of transporters. \*Cytochrome P450 inducers\* A CYP3A4 inducer, rifampicin, reduced tadalafil AUC by 88%, relative to the AUC values for tadalafil alone (10mg). 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 tadalafil. \*\*Effects of Tadalafil on Other Medicinal Products\*\* \*Nitrates\* In clinical studies, tadalafil (5mg, 10mg and 20mg) 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 20mg for 7 days and 0.4mg 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 (2.5mg - 20mg), 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 and 8mg daily) and tadalafil (5mg daily dose and 20mg 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. 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 (10mg, except for studies with angiotensin II receptor blockers and amlodipine in which a 20mg dose was applied) had no clinically significant interaction with any of these classes. In another clinical pharmacology study, tadalafil (20mg) 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 20mg 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 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 coadministered with finasteride 5 mg to placebo plus finasteride 5 mg in the relief of BPH symptoms, no new adverse reactions were identified. However, as a formal drug-drug 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 10mg 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. \*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\* Alcohol concentrations (mean maximum blood concentration 0.08%) were not affected by co-administration with tadalafil (10mg or 20mg). 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 (20mg) did not augment the mean blood pressure decrease produced by alcohol (0.7g/kg or approximately 180ml 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 (0.6g/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 (10mg). \*Cytochrome P450 metabolised medicinal products\* Tadalafil is not expected to cause clinically significant inhibition or induction of the clearance of medicinal products metabolised by CYP450 isoforms. Studies have confirmed that tadalafil does not inhibit or induce CYP450 isoforms, including CYP3A4, CYP1A2, CYP2D6, CYP2E1, CYP2C9 and CYP2C19. \*CYP2C9 substrates (e.g. R-warfarin)\* Tadalafil (10mg and 20mg) 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 (10mg and 20mg) did not potentiate the increase in bleeding time caused by acetylsalicylic acid. \*Antidiabetic medicinal products\* Specific interaction studies with antidiabetic medicinal products were not conducted.4.6 Fertility, pregnancy and lactation Tadalafil 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. \*\*Breastfeeding\*\* 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).4.7 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 trials was similar, patients should be aware of how they react to Tadalafil before driving or using machines.4.8 Undesirable effects \*\*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 (comprising a total of 8022 patients on Tadalafil and 4422 patients on placebo) for on-demand and once-a-day treatment of erectile dysfunction Frequency convention: 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 (cannot be estimated from the available data). | | | | | | --- | --- | --- | --- | | \*\*Very common\*\* | \*\*Common\*\* | \*\*Uncommon\*\* | \*\*Rare\*\* | | \*Immune system disorders\* | | | | | | | Hypersensitivity reactions | Angioedema2 | | \*Nervous system disorders\* | | | | | | Headache | Dizziness | Stroke1 (including haemorrhagic events), Syncope, Transient ischaemic attacks1, Migraine2, 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)2, Retinal vascular occlusion2 | | \*Ear and labyrinth disorders\* | | | | | | | Tinnitus | Sudden hearing loss | | \*Cardiac disorders1\* | | | | | | | Tachycardia, Palpitations | Myocardial infarction, Unstable angina pectoris2, Ventricular arrhythmia2 | | \*Vascular disorders\* | | | | | | Flushing | Hypotension3, 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 syndrome2, Exfoliative dermatitis2, Hyperhydrosis (sweating) | | \*Renal and urinary disorders\* | | | | | | | Haematuria | | | \*Musculoskeletal, connective tissue and bone disorders\* | | | | | | Back pain, Myalgia, Pain in extremity | | | | \*Reproductive system and breast disorders\* | | | | | | | Prolonged erections | Priapism, Penile haemorrhage, Haematospermia | | \*General disorders and administration site conditions\* | | | | | | | Chest pain1, Peripheral oedema, Fatigue | Facial oedema2, Sudden cardiac death1,2 | 1 Most of the patients had pre-existing cardiovascular risk factors (see section 4.4). 2 Postmarketing 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. \*\*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. \*\*Other special populations\*\* Data in patients over 65 years of age receiving tadalafil in clinical trials, for the treatment of erectile dysfunction, are limited. 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. \*\*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 via the Yellow Card Scheme (www.mhra.gov.uk/yellowcard).4.9 Overdose Single doses of up to 500mg have been given to healthy subjects, and multiple daily doses up to 100mg 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.
Instruction Pharmacology: 5.1 Pharmacodynamic properties Pharmacotherapeutic group: Urologicals, Drugs used in erectile dysfunction. ATC code: G04BE08. \*\*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 absence of sexual stimulation. \*\*Pharmacodynamic 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 phototransduction. Tadalafil is also >10,000-fold more potent for PDE5 than for PDE7 through PDE10. \*\*Clinical efficacy and safety\*\* Three clinical studies were conducted in 1054 patients in an at-home setting to define the period of responsiveness to Tadalafil. Tadalafil demonstrated statistically significant improvement in erectile function and the ability to have successful sexual intercourse up to 36 hours following dosing, as well as patients' ability to attain and maintain erections for successful intercourse compared to placebo as early as 16 minutes following dosing. Tadalafil administered to healthy subjects produced no significant difference compared to placebo in supine systolic and diastolic blood pressure (mean maximal decrease of 1.6/0.8mmHg, respectively), in standing systolic and diastolic blood pressure (mean maximal decrease of 0.2/4.6mmHg, respectively), 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. Across all clinical studies, reports of changes in colour vision were rare (<0.1%). Three studies were conducted in men to assess the potential effect on spermatogenesis of Tadalafil 10mg (one 6-month study) and 20mg (one 6-month and one 9-month study) administered daily. In two of these studies decreases were observed in sperm count and concentration related to tadalafil treatment of unlikely clinical relevance. These effects were not associated with changes in other parameters, such as motility, morphology, and FSH. Tadalafil at doses of 2 to 100mg 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 Tadalafil improved their erections as compared to 35% with placebo. Also, patients with erectile dysfunction in all severity categories reported improved erections whilst taking Tadalafil (86%, 83%, and 72% for mild, moderate, and severe, respectively, as compared to 45%, 42%, and 19% with placebo). In the primary efficacy studies, 75% of intercourse attempts were successful in Tadalafil -treated patients as compared to 32% with placebo. In a 12-week study performed in 186 patients (142 tadalafil, 44 placebo) with erectile dysfunction secondary to spinal cord injury, tadalafil significantly improved the erectile function leading to a mean per-subject proportion of successful attempts in patients treated with tadalafil 10 or 20 mg (flexible-dose, on demand) of 48% as compared to 17% with placebo. \*\*Paediatric population\*\* A single study has been performed in paediatric patients with Duchenne Muscular Dystrophy (DMD) in which no evidence of efficacy was seen. The randomised, double-blind, placebo-controlled, parallel, 3-arm study of tadalafil was conducted in 331 boys aged 7-14 years with DMD receiving concurrent corticosteroid therapy. The study included a 48-week double-blind period where patients were randomised to tadalafil 0.3 mg/kg, tadalafil 0.6 mg/kg, or placebo daily. Tadalafil did not show efficacy in slowing the decline in ambulation as measured by the primary 6 minute walk distance (6MWD) endpoint: least squares (LS) mean change in 6MWD at 48 weeks was -51.0 meters (m) in the placebo group, compared with -64.7 m in the tadalafil 0.3 mg/kg group (p = 0.307) and -59.1 m in the tadalafil 0.6 mg/kg group (p = 0.538). In addition, there was no evidence of efficacy from any of the secondary analyses performed in this study. The overall safety results from this study were generally consistent with the known safety profile of tadalafil and with adverse events (AEs) expected in a paediatric DMD population receiving corticosteroids. The European Medicines Agency has waived the obligation to submit the results of studies in all subsets of the paediatric population in the treatment of the erectile dysfunction. See section 4.2 for information on paediatric use.5.2 Pharmacokinetic properties \*\*Absorption\*\* Tadalafil is readily absorbed after oral administration and the mean maximum observed plasma concentration (Cmax) is achieved at a median 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, this 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 63l, indicating that Tadalafil is distributed into tissues. At therapeutic concentrations, 94% of tadalafil in plasma is bound in 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 2.5l/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). \*\*Linearity/non-linearity\*\* Tadalafil pharmacokinetics in healthy subjects are linear with respect to time and dose. Over a dose range of 2.5 to 20mg, 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 are similar to pharmacokinetics in subjects without erectile dysfunction. \*\*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 clinical pharmacology studies using single dose tadalafil (5mg-20mg), tadalafil exposure (AUC) approximately doubled in subjects with mild (creatinine clearance 51 to 80ml/min) or moderate (creatinine clearance 31 to 50ml/min) renal impairment and in subjects with end-stage renal disease on dialysis. In haemodialysis patients, Cmax was 41% higher than that observed in healthy subjects. Haemodialysis 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 10mg 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 10mg of tadalafil to patients with hepatic impairment. \*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.5.3 Preclinical safety data Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, and toxicity to reproduction. There was no evidence of teratogenicity, embryotoxicity, or foetotoxicity in rats or mice that received up to 1000mg/kg/day tadalafil. In a rat prenatal and postnatal development study, the no observed effect dose was 30mg/kg/day. In the pregnant rat the AUC for calculated free drug at this dose was approximately 18-times the human AUC at a 20mg dose. There was no impairment of fertility in male and female rats. In dogs given tadalafil daily for 6 to 12 months at doses of 25mg/kg/day (resulting in at least a 3-fold greater exposure [range 3.7-18.6] than seen in humans given a single 20mg dose) and above, there was regression of the seminiferous tubular epithelium that resulted in a decrease in spermatogenesis in some dogs. See also section 5.1.
Instruction Pharmaceutical Particulars: 6.1 List of excipients \*\*Tablet core:\*\* Hydroxypropyl cellulose (E463) Lactose monohydrate Croscarmellose sodium (E468) Sodium lauryl sulfate Povidone K-25 Silica colloidal anhydrous Magnesium stearate (E572) \*\*Film coating:\*\* Hypromellose (E464) Titanium Dioxide (E171) Macrogol Talc Iron Oxide Yellow (E172)6.2 Incompatibilities Not applicable.6.3 Shelf life 36 months6.4 Special precautions for storage This product does not require any special temperature storage conditions.6.5 Nature and contents of container Aluminium foil and PVC/Aclar film blisters, OR Aluminium foil and CFB foil blisters in cartons of 2, 4, 8, 10, 12, 14, 28 or 84 film-coated tablets. Not all pack sizes may be marketed.6.6 Special precautions for disposal and other handling Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
Instruction Content: ## Composition Each 10mg tablet contains 10mg tadalafil. \*\*Excipient(s) with known effect\*\* Each coated tablet contains 163.40mg of lactose (as monohydrate). For the full list of excipients, see section 6.1. ## Pharmaceutical Form Film-coated tablet. The 10mg tablets are light yellow to yellow, round shaped, film-coated tablets imprinted with '338' on one side. ## Clinical Particulars 4.1 Therapeutic indications Treatment of erectile dysfunction in adult males. In order for Tadalafil to be effective, sexual stimulation is required. Tadalafil is not indicated for use by women.4.2 Posology and method of administration \*\*Posology\*\* \*Adult men\* In general, the recommended dose is 10mg taken prior to anticipated sexual activity and with or without food. In those patients in whom Tadalafil 10mg does not produce an adequate effect, 20mg might be tried. It may be taken at least 30 minutes prior to sexual activity. The maximum dose frequency is once per day. Tadalafil 10mg and 20mg is 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 (i.e., at least twice weekly) a once daily regimen with the lowest doses of Tadalafil might be considered suitable, based on patient choice and the physician's judgement. In these patients, the recommended dose is 5mg taken once a day at approximately the same time of day. The dose may be decreased to 2.5mg once a day based on individual tolerability. The appropriateness of continued use of the daily regimen should be reassessed periodically. \*\*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, 10mg is the maximum recommended dose. Once-a-day dosing tadalafil is not recommended in patients with severe renal impairment. (See sections 4.4 and 5.2.) \*Men with Hepatic Impairment\* The recommended dose of Tadalafil is 10mg taken prior to anticipated sexual activity and with or without food. There is limited clinical data on the safety of Tadalafil 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 10mg of tadalafil to patients with hepatic impairment. Once-a-day dosing has not been evaluated in patients with hepatic impairment; therefore, if prescribed, a careful individual benefit/risk evaluation should be undertaken by the prescribing physician. (See sections 4.4 and 5.2.) \*Men with Diabetes\* Dose adjustments are not required in diabetic patients. \*Paediatric population\* There is no relevant use of Tadalafil in the paediatric population with regard to the treatment of erectile dysfunction. \*\*Method of administration\*\* For oral use.4.3 Contraindications Hypersensitivity to the active substance 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.) Tadalafil, 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 (<90/50mmHg), 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). 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).4.4 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 (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 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, to sexual activity, or to a combination of these or other factors. 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 Tadalafil and consult a physician 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 tadalafil and seek prompt medical attention in the event of sudden decrease or loss of hearing. \*\*Hepatic 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). If Tadalafil is prescribed, a careful individual benefit/risk evaluation should be undertaken by the prescribing physician. \*\*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, 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 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\*\* Tadalafil contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.4.5 Interaction with other medicinal products and other forms of interaction Interaction studies were conducted with 10mg and/or 20mg tadalafil, as indicated below. With regard to those interaction studies where only the 10mg tadalafil dose was used, clinically relevant interactions at higher doses cannot be completely ruled out. \*\*Effects of Other Substances on Tadalafil\*\* \*Cytochrome P450 inhibitors\* Tadalafil is principally metabolised by CYP3A4. A selective inhibitor of CYP3A4, ketoconazole (200mg daily), increased tadalafil (10mg) exposure (AUC) 2-fold and Cmax by 15%, relative to the AUC and Cmax values for tadalafil alone. Ketoconazole (400mg daily) increased tadalafil (20mg) exposure (AUC) 4-fold and Cmax by 22%. Ritonavir, a protease inhibitor (200mg twice daily), which is an inhibitor of CYP3A4, CYP2C9, CYP2C19, and CYP2D6, increased tadalafil (20mg) exposure (AUC) 2-fold with no change in Cmax. 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 drug interactions mediated by inhibition of transporters. \*Cytochrome P450 inducers\* A CYP3A4 inducer, rifampicin, reduced tadalafil AUC by 88%, relative to the AUC values for tadalafil alone (10mg). 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 tadalafil. \*\*Effects of Tadalafil on Other Medicinal Products\*\* \*Nitrates\* In clinical studies, tadalafil (5mg, 10mg and 20mg) 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 20mg for 7 days and 0.4mg 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 (2.5mg - 20mg), 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 and 8mg daily) and tadalafil (5mg daily dose and 20mg 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. 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 (10mg, except for studies with angiotensin II receptor blockers and amlodipine in which a 20mg dose was applied) had no clinically significant interaction with any of these classes. In another clinical pharmacology study, tadalafil (20mg) 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 20mg 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 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 coadministered with finasteride 5 mg to placebo plus finasteride 5 mg in the relief of BPH symptoms, no new adverse reactions were identified. However, as a formal drug-drug 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 10mg 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. \*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\* Alcohol concentrations (mean maximum blood concentration 0.08%) were not affected by co-administration with tadalafil (10mg or 20mg). 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 (20mg) did not augment the mean blood pressure decrease produced by alcohol (0.7g/kg or approximately 180ml 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 (0.6g/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 (10mg). \*Cytochrome P450 metabolised medicinal products\* Tadalafil is not expected to cause clinically significant inhibition or induction of the clearance of medicinal products metabolised by CYP450 isoforms. Studies have confirmed that tadalafil does not inhibit or induce CYP450 isoforms, including CYP3A4, CYP1A2, CYP2D6, CYP2E1, CYP2C9 and CYP2C19. \*CYP2C9 substrates (e.g. R-warfarin)\* Tadalafil (10mg and 20mg) 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 (10mg and 20mg) did not potentiate the increase in bleeding time caused by acetylsalicylic acid. \*Antidiabetic medicinal products\* Specific interaction studies with antidiabetic medicinal products were not conducted.4.6 Fertility, pregnancy and lactation Tadalafil 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. \*\*Breastfeeding\*\* 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).4.7 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 trials was similar, patients should be aware of how they react to Tadalafil before driving or using machines.4.8 Undesirable effects \*\*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 (comprising a total of 8022 patients on Tadalafil and 4422 patients on placebo) for on-demand and once-a-day treatment of erectile dysfunction Frequency convention: 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 (cannot be estimated from the available data). | | | | | | --- | --- | --- | --- | | \*\*Very common\*\* | \*\*Common\*\* | \*\*Uncommon\*\* | \*\*Rare\*\* | | \*Immune system disorders\* | | | | | | | Hypersensitivity reactions | Angioedema2 | | \*Nervous system disorders\* | | | | | | Headache | Dizziness | Stroke1 (including haemorrhagic events), Syncope, Transient ischaemic attacks1, Migraine2, 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)2, Retinal vascular occlusion2 | | \*Ear and labyrinth disorders\* | | | | | | | Tinnitus | Sudden hearing loss | | \*Cardiac disorders1\* | | | | | | | Tachycardia, Palpitations | Myocardial infarction, Unstable angina pectoris2, Ventricular arrhythmia2 | | \*Vascular disorders\* | | | | | | Flushing | Hypotension3, 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 syndrome2, Exfoliative dermatitis2, Hyperhydrosis (sweating) | | \*Renal and urinary disorders\* | | | | | | | Haematuria | | | \*Musculoskeletal, connective tissue and bone disorders\* | | | | | | Back pain, Myalgia, Pain in extremity | | | | \*Reproductive system and breast disorders\* | | | | | | | Prolonged erections | Priapism, Penile haemorrhage, Haematospermia | | \*General disorders and administration site conditions\* | | | | | | | Chest pain1, Peripheral oedema, Fatigue | Facial oedema2, Sudden cardiac death1,2 | 1 Most of the patients had pre-existing cardiovascular risk factors (see section 4.4). 2 Postmarketing 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. \*\*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. \*\*Other special populations\*\* Data in patients over 65 years of age receiving tadalafil in clinical trials, for the treatment of erectile dysfunction, are limited. 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. \*\*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 via the Yellow Card Scheme (www.mhra.gov.uk/yellowcard).4.9 Overdose Single doses of up to 500mg have been given to healthy subjects, and multiple daily doses up to 100mg 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. ## Pharmacological Properties 5.1 Pharmacodynamic properties Pharmacotherapeutic group: Urologicals, Drugs used in erectile dysfunction. ATC code: G04BE08. \*\*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 absence of sexual stimulation. \*\*Pharmacodynamic 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 phototransduction. Tadalafil is also >10,000-fold more potent for PDE5 than for PDE7 through PDE10. \*\*Clinical efficacy and safety\*\* Three clinical studies were conducted in 1054 patients in an at-home setting to define the period of responsiveness to Tadalafil. Tadalafil demonstrated statistically significant improvement in erectile function and the ability to have successful sexual intercourse up to 36 hours following dosing, as well as patients' ability to attain and maintain erections for successful intercourse compared to placebo as early as 16 minutes following dosing. Tadalafil administered to healthy subjects produced no significant difference compared to placebo in supine systolic and diastolic blood pressure (mean maximal decrease of 1.6/0.8mmHg, respectively), in standing systolic and diastolic blood pressure (mean maximal decrease of 0.2/4.6mmHg, respectively), 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. Across all clinical studies, reports of changes in colour vision were rare (<0.1%). Three studies were conducted in men to assess the potential effect on spermatogenesis of Tadalafil 10mg (one 6-month study) and 20mg (one 6-month and one 9-month study) administered daily. In two of these studies decreases were observed in sperm count and concentration related to tadalafil treatment of unlikely clinical relevance. These effects were not associated with changes in other parameters, such as motility, morphology, and FSH. Tadalafil at doses of 2 to 100mg 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 Tadalafil improved their erections as compared to 35% with placebo. Also, patients with erectile dysfunction in all severity categories reported improved erections whilst taking Tadalafil (86%, 83%, and 72% for mild, moderate, and severe, respectively, as compared to 45%, 42%, and 19% with placebo). In the primary efficacy studies, 75% of intercourse attempts were successful in Tadalafil -treated patients as compared to 32% with placebo. In a 12-week study performed in 186 patients (142 tadalafil, 44 placebo) with erectile dysfunction secondary to spinal cord injury, tadalafil significantly improved the erectile function leading to a mean per-subject proportion of successful attempts in patients treated with tadalafil 10 or 20 mg (flexible-dose, on demand) of 48% as compared to 17% with placebo. \*\*Paediatric population\*\* A single study has been performed in paediatric patients with Duchenne Muscular Dystrophy (DMD) in which no evidence of efficacy was seen. The randomised, double-blind, placebo-controlled, parallel, 3-arm study of tadalafil was conducted in 331 boys aged 7-14 years with DMD receiving concurrent corticosteroid therapy. The study included a 48-week double-blind period where patients were randomised to tadalafil 0.3 mg/kg, tadalafil 0.6 mg/kg, or placebo daily. Tadalafil did not show efficacy in slowing the decline in ambulation as measured by the primary 6 minute walk distance (6MWD) endpoint: least squares (LS) mean change in 6MWD at 48 weeks was -51.0 meters (m) in the placebo group, compared with -64.7 m in the tadalafil 0.3 mg/kg group (p = 0.307) and -59.1 m in the tadalafil 0.6 mg/kg group (p = 0.538). In addition, there was no evidence of efficacy from any of the secondary analyses performed in this study. The overall safety results from this study were generally consistent with the known safety profile of tadalafil and with adverse events (AEs) expected in a paediatric DMD population receiving corticosteroids. The European Medicines Agency has waived the obligation to submit the results of studies in all subsets of the paediatric population in the treatment of the erectile dysfunction. See section 4.2 for information on paediatric use.5.2 Pharmacokinetic properties \*\*Absorption\*\* Tadalafil is readily absorbed after oral administration and the mean maximum observed plasma concentration (Cmax) is achieved at a median 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, this 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 63l, indicating that Tadalafil is distributed into tissues. At therapeutic concentrations, 94% of tadalafil in plasma is bound in 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 2.5l/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). \*\*Linearity/non-linearity\*\* Tadalafil pharmacokinetics in healthy subjects are linear with respect to time and dose. Over a dose range of 2.5 to 20mg, 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 are similar to pharmacokinetics in subjects without erectile dysfunction. \*\*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 clinical pharmacology studies using single dose tadalafil (5mg-20mg), tadalafil exposure (AUC) approximately doubled in subjects with mild (creatinine clearance 51 to 80ml/min) or moderate (creatinine clearance 31 to 50ml/min) renal impairment and in subjects with end-stage renal disease on dialysis. In haemodialysis patients, Cmax was 41% higher than that observed in healthy subjects. Haemodialysis 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 10mg 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 10mg of tadalafil to patients with hepatic impairment. \*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.5.3 Preclinical safety data Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, and toxicity to reproduction. There was no evidence of teratogenicity, embryotoxicity, or foetotoxicity in rats or mice that received up to 1000mg/kg/day tadalafil. In a rat prenatal and postnatal development study, the no observed effect dose was 30mg/kg/day. In the pregnant rat the AUC for calculated free drug at this dose was approximately 18-times the human AUC at a 20mg dose. There was no impairment of fertility in male and female rats. In dogs given tadalafil daily for 6 to 12 months at doses of 25mg/kg/day (resulting in at least a 3-fold greater exposure [range 3.7-18.6] than seen in humans given a single 20mg dose) and above, there was regression of the seminiferous tubular epithelium that resulted in a decrease in spermatogenesis in some dogs. See also section 5.1. ## Pharmaceutical Particulars 6.1 List of excipients \*\*Tablet core:\*\* Hydroxypropyl cellulose (E463) Lactose monohydrate Croscarmellose sodium (E468) Sodium lauryl sulfate Povidone K-25 Silica colloidal anhydrous Magnesium stearate (E572) \*\*Film coating:\*\* Hypromellose (E464) Titanium Dioxide (E171) Macrogol Talc Iron Oxide Yellow (E172)6.2 Incompatibilities Not applicable.6.3 Shelf life 36 months6.4 Special precautions for storage This product does not require any special temperature storage conditions.6.5 Nature and contents of container Aluminium foil and PVC/Aclar film blisters, OR Aluminium foil and CFB foil blisters in cartons of 2, 4, 8, 10, 12, 14, 28 or 84 film-coated tablets. Not all pack sizes may be marketed.6.6 Special precautions for disposal and other handling Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

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Agency

UK EMC

Country

🇬🇧

Approval ID

b7d64d50d310b463

Type

Standard

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