Article Contents
- 1. NAME OF THE MEDICINAL PRODUCT
- 2. QUALITATIVE AND QUANTITATIVE COMPOSITION
- 3. PHARMACEUTICAL FORM
- 4. CLINICAL PARTICULARS
- 4.1 Therapeutic indications
- 4.2 Posology and method of administration
- 4.3 Contraindications
- 4.4 Special warnings and precautions for use
- 4.5 Interaction with other medicinal products and other forms of interaction
- 4.6 Fertility, pregnancy and lactation
- 4.7 Effects on ability to drive and use machines
- 4.8 Undesirable effects
- 4.9 Overdose
- 5. PHARMACOLOGICAL PROPERTIES
- 6. PHARMACEUTICAL PARTICULARS
- 7. MARKETING AUTHORISATION HOLDER
- 8. MARKETING AUTHORISATION NUMBER(S)
- 9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
- 10. DATE OF REVISION OF THE TEXT
1.NAME OF THE MEDICINAL PRODUCT
Tadalafil Mylan 2.5 mg
2.QUALITATIVE AND QUANTITATIVE COMPOSITION
Each tablet contains 2.5 mg tadalafil.
Excipient with known effect:
Each coated tablet contains 29.74 mg of lactose.
For the full list of excipients, see section 6.1.
3.PHARMACEUTICAL FORM
A light yellow,
4.CLINICAL PARTICULARS
4.1Therapeutic indications
Treatment of erectile dysfunction in adult males.
In order for tadalafil to be effective, sexual stimulation is required.
Tadalafil Mylan is not indicated for use by women.
4.2Posology and method of administration
Posology
Adult men
In general, the recommended dose is 10 mg taken prior to anticipated sexual activity and with or without food.
In those patients in whom tadalafil 10 mg does not produce an adequate effect, 20 mg might be tried. It may be taken at least 30 minutes prior to sexual activity.
The maximum dose frequency is once per day.
Tadalafil 10 and 20 mg 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 5 mg taken once a day at approximately the same time of day. The dose may be decreased to 2.5 mg once a day based on individual tolerability.
The appropriateness of continued use of the daily regimen should be reassessed periodically.
Special populations
Elderly men
Dose adjustments are not required in elderly patients.
Men with renal impairment
Dose adjustments are not required in patients with mild to moderate renal impairment. For patients with severe renal impairment 10 mg is the maximum recommended dose.
Men with hepatic impairment
The recommended dose of tadalafil is 10 mg 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
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
Tadalafil Mylan is available as 2.5, 5, 10, and 20 mg
4.3Contraindications
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
The following groups of patients with cardiovascular disease were not included in clinical trials and the use of tadalafil is therefore contraindicated:
-patients with myocardial infarction within the last 90 days,
-patients with unstable angina or angina occurring during sexual intercourse,
-patients with New York Heart Association Class 2 or greater heart failure in the last 6 months,
-patients with uncontrolled arrhythmias, hypotension (< 90/50 mm Hg), 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
The
4.4Special warnings and precautions for use
Before treatment with Tadalafil Mylan
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
Cardiovascular
Serious cardiovascular events, including myocardial infarction, sudden cardiac death, unstable angina pectoris, ventricular arrhythmia, stroke, transient ischemic attacks, chest pain, palpitations and tachycardia, have been reported either post marketing and/or in clinical trials. Most of the patients in whom these events have been reported had
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 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 Mylan 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.
Renal and hepatic impairment
Due to increased tadalafil exposure (AUC), limited clinical experience and the lack of ability to influence clearance by dialysis,
There is limited clinical data on the safety of
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 Mylan in such combinations.
Lactose
Tadalafil Mylan contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or
4.5Interaction with other medicinal products and other forms of interaction
Interaction studies were conducted with 10 mg and/or 20 mg tadalafil, as indicated below. With regard to those interaction studies where only the 10 mg tadalafil dose was used, clinically relevant interactions at higher doses cannot be completely ruled out.
Effects of other substances on tadalafil
Cytochrome P450 inhibitors
Tadalafil is principally metabolised by CYP3A4. A selective inhibitor of CYP3A4, ketoconazole (200 mg daily), increased tadalafil (10 mg) exposure (AUC)
Consequently the incidence of the adverse reactions listed in section 4.8 might be increased.
Transporters
The role of transporters (for example
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 phenobarbital, phenytoin and carbamazepine, may also decrease plasma concentrations of tadalafil.
Effects of tadalafil on other medicinal products
Nitrates
In clinical studies, tadalafil (5, 10 and 20 mg) was shown to augment the hypotensive effects of nitrates. 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 (2.5
The
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
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),
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
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).
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
CYP1A2 substrates (e.g. theophylline)
When tadalafil 10 mg was administered with theophylline (a
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
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
(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 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.
Tadalafil (10 mg and 20 mg) had no clinically significant effect on exposure (AUC) to
Aspirin
Tadalafil (10 mg and 20 mg) did not potentiate the increase in bleeding time caused by acetyl salicylic acid.
Antidiabetic medicinal products
Specific interaction studies with antidiabetic medicinal products were not conducted.
4.6Fertility, pregnancy and lactation
Tadalafil Mylan 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 Mylan 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 Mylan 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).
4.7Effects 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.
4.8Undesirable effects
Summary of the safety profile
The most commonly reported adverse reactions in patients taking tadalafil for the treatment of erectile dysfunction or benign prostatic hyperplasia 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
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
Frequency convention: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000), very rare (<1/10,000) and not known (cannot be estimated from the available data).
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, |
|
|
| Seizures2, |
|
|
| Transient amnesia |
|
|
|
|
Eye disorders |
|
|
|
|
|
|
|
|
| Blurred vision, | Visual field defect, |
|
| Sensations described as | Swelling of eyelids, |
|
| eye pain | Conjunctival hyperaemia, |
|
|
| |
|
|
| optic neuropathy (NAION)2, |
|
|
| Retinal vascular occlusion2 |
|
|
|
|
Ear and labyrinth disorders |
|
| |
|
|
|
|
|
| Tinnitus | Sudden hearing loss |
|
|
|
|
Cardiac disorders1 |
|
|
|

Tachycardia, | Myocardial infarction, |
Palpitations | Unstable angina pectoris2, |
| Ventricular arrhythmia2 |
Vascular disorders |
|
| |
| Flushing | Hypotension3, |
|
|
| Hypertension |
|
Respiratory, thoracic and mediastinal disorders |
| ||
|
|
|
|
| Nasal | Dyspnoea, |
|
| congestion | Epistaxis |
|
|
|
|
|
Gastrointestinal disorders |
|
|
|
| Dyspepsia | Abdominal pain, |
|
|
| Vomiting, Nausea, |
|
|
|
| |
Skin and subcutaneous | tissue disorders |
|
|
|
|
|
|
|
| Rash | Urticaria, |
|
|
| |
|
|
| Exfoliative dermatitis2, |
|
|
| Hyperhydrosis (sweating) |
|
|
|
|
Musculoskeletal and connective tissue 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 pain1, Peripheral | Facial oedema2, |
|
| oedema, Fatigue | Sudden cardiac death1, 2 |
(1)Most of the patients had
(2)Postmarketing surveillance reported adverse reactions not observed in
(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, either for the treatment of erectile dysfunction or the treatment of benign prostatic hyperplasia, are limited. In clinical trials with tadalfil 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 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 national reporting system listed in Appendix V.
4.9Overdose
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.
5.PHARMACOLOGICAL PROPERTIES
5.1Pharmacodynamic 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
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 >
This selectivity for PDE5 over PDE3 is important because PDE3 is an enzyme involved in cardiac contractility. Additionally, tadalafil is approximately
Clinical efficacy and safety
Three clinical studies were conducted in 1054 patients in an
Tadalafil administered to healthy subjects produced no significant difference compared to placebo in supine systolic and diastolic blood pressure (mean maximal decrease of 1.6/0.8 mm Hg, respectively), in standing systolic and diastolic blood pressure (mean maximal decrease of 0.2/4.6 mm Hg, 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
Three studies were conducted in men to assess the potential effect on spermatogenesis of tadalafil 10 mg (one
Tadalafil at doses of 2.5, 5, and 10 mg taken once a day was initially evaluated in 3 clinical studies involving 853 patients of various ages (range
217 patients who were
In a
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,
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
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.
5.2Pharmacokinetic 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, thus tadalafil may be taken with or without food. The time of dosing (morning versus evening) had no clinically relevant effects on the rate and extent of absorption.
Distribution
The mean volume of distribution is approximately 63 l, indicating that tadalafil is distributed into tissues. At therapeutic concentrations, 94% of tadalafil in plasma is bound to proteins. Protein binding is not affected by impaired renal function.
Less than 0.0005% of the administered dose appeared in the semen of healthy subjects.
Biotransformation
Tadalafil is predominantly metabolised by the cytochrome P450 (CYP) 3A4 isoform. The major circulating metabolite is the methylcatechol glucuronide. This metabolite is at least
Elimination
The mean oral clearance for tadalafil is 2.5 l/h and the mean
Tadalafil pharmacokinetics in healthy subjects are linear with respect to time and dose. Over a dose range of 2.5 to 20 mg, exposure (AUC) increases proportionally with dose.
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
Hepatic insufficiency
Tadalafil exposure (AUC) in subjects with mild and moderate 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.
5.3Preclinical safety data
- Talmanco (tadalafil generics) - tadalafil
- Cialis - tadalafil
- Adcirca (tadalafil lilly) - tadalafil
- Tadalafil generics - tadalafil
- Tadalafil lilly - tadalafil
Prescription drugs listed. Substance: "Tadalafil"
There was no evidence of teratogenicity, embryotoxicity or foetotoxicity in rats or mice that received up to 1000 mg/kg/day tadalafil. In a rat prenatal and postnatal development study, the no observed effect dose was
30 mg/kg/day. In the pregnant rat the AUC for calculated free drug at this dose was approximately 18 times the human AUC at a 20 mg 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 25 mg/kg/day (resulting in at least a
6.PHARMACEUTICAL PARTICULARS
6.1List of excipients
Tablet core:
Lactose, anhydrous
Poloxamer 188
Cellulose, microcrystalline (pH101)
Povidone
Croscarmellose sodium
Magnesium stearate
Sodium laurilsulfate
Silica, colloidal anhydrous
Lactose monohydrate
Hypromellose (E464)
Titanium dioxide (E171)
Iron oxide yellow (E172)
Triacetin
6.2Incompatibilities
Not applicable.
6.3Shelf life
3 years
6.4Special precautions for storage
This medicinal product does not require any special storage conditions.
6.5Nature and contents of container
Pack sizes of 28 and 56 tablets.
Not all pack sizes may be marketed.
6.6Special precautions for disposal
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
7.MARKETING AUTHORISATION HOLDER
Generics [UK] Limited
Station Close
Potters Bar
Hertfordshire
EN6 1TL
United Kingdom
8.MARKETING AUTHORISATION NUMBER(S)
EU/1/14/961/008
EU/1/14/961/009
9.DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
Date of first authorisation: 21 November 2014
10.DATE OF REVISION OF THE TEXT
Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu.
1. NAME OF THE MEDICINAL PRODUCT
Tadalafil Mylan 5 mg
2. QUALITATIVE AND QUANTITATIVE COMPOSITION
Each tablet contains 5 mg tadalafil.
Excipient with known effect:
Each coated tablet contains 59.48 mg of lactose.
For the full list of excipients, see section 6.1.
3. PHARMACEUTICAL FORM
A light yellow,
4. CLINICAL PARTICULARS
4.1 Therapeutic indications
Treatment of erectile dysfunction in adult males.
In order for tadalafil to be effective for the treatment of erectile dysfunction, sexual stimulation is required.
Treatment of the signs and symptoms of benign prostatic hyperplasia in adult males.
Tadalafil Mylan is not indicated for use by women.
4.2 Posology and method of administration
Posology
Erectile dysfunction in adult men
In general, the recommended dose is 10 mg taken prior to anticipated sexual activity and with or without food.
In those patients in whom tadalafil 10 mg does not produce an adequate effect, 20 mg might be tried. It may be taken at least 30 minutes prior to sexual activity.
The maximum dose frequency is once per day.
Tadalafil 10 and 20 mg 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 5 mg taken once a day at approximately the same time of day. The dose may be decreased to 2.5 mg once a day based on individual tolerability.
The appropriateness of continued use of the daily regimen should be reassessed periodically.
Benign prostatic hyperplasia in adult men
The recommended dose is 5 mg, taken at approximately the same time every day with or without food. For adult men being treated for both benign prostatic hyperplasia and erectile dysfunction the recommended dose is also 5 mg taken at approximately the same time every day. Patients who are unable to tolerate tadalafil
5 mg for the treatment of benign prostatic hyperplasia should consider an alternative therapy as the efficacy of tadalafil 2.5 mg for the treatment of benign prostatic hyperplasia has not been demonstrated.
Special populations
Elderly men
Dose adjustments are not required in elderly patients.
Men with renal impairment
Dose adjustments are not required in patients with mild to moderate renal impairment. For patients with severe renal impairment 10 mg is the maximum recommended dose for
Men with hepatic impairment
For the treatment of erectile dysfunction using
10 mg 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
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
Tadalafil Mylan is available as 2.5, 5, 10, and 20 mg
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
The following groups of patients with cardiovascular disease were not included in clinical trials and the use of tadalafil is therefore contraindicated:
-patients with myocardial infarction within the last 90 days,
-patients with unstable angina or angina occurring during sexual intercourse,
-patients with New York Heart Association Class 2 or greater heart failure in the last 6 months,
-patients with uncontrolled arrhythmias, hypotension (< 90/50 mm Hg), 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
The
4.4 Special warnings and precautions for use
Before treatment with Tadalafil Mylan
A medical history and physical examination should be undertaken to diagnose erectile dysfunction or benign prostatic hyperplasia 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).
Prior to initiating treatment with tadalafil for benign prostatic hyperplasia patients should be examined to rule out the presence of carcinoma of the prostate and carefully assessed for cardiovascular conditions (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
Cardiovascular
Serious cardiovascular events, including myocardial infarction, sudden cardiac death, unstable angina pectoris, ventricular arrhythmia, stroke, transient ischemic attacks, chest pain, palpitations and tachycardia, have been reported either post marketing and/or in clinical trials. Most of the patients in whom these events have been reported had
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 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 Mylan 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.
Renal and hepatic impairment
Due to increased tadalafil exposure (AUC), limited clinical experience and the lack of ability to influence clearance by dialysis,
There is limited clinical data on the safety of
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 Mylan in such combinations.
Lactose
Tadalafil Mylan contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or
4.5 Interaction with other medicinal products and other forms of interaction
Interaction studies were conducted with 10 mg and/or 20 mg tadalafil, as indicated below. With regard to those interaction studies where only the 10 mg tadalafil dose was used, clinically relevant interactions at higher doses cannot be completely ruled out.
Effects of other substances on tadalafil
Cytochrome P450 inhibitors
Tadalafil is principally metabolised by CYP3A4. A selective inhibitor of CYP3A4, ketoconazole (200 mg daily), increased tadalafil (10 mg) exposure (AUC)
Consequently the incidence of the adverse reactions listed in section 4.8 might be increased.
Transporters
The role of transporters (for example
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 phenobarbital, phenytoin and carbamazepine, may also decrease plasma concentrations of tadalafil.
Effects of tadalafil on other medicinal products
Nitrates
In clinical studies, tadalafil (5, 10 and 20 mg) was shown to augment the hypotensive effects of nitrates. 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 (2.5
The
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
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),
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).
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
CYP1A2 substrates (e.g. theophylline)
When tadalafil 10 mg was administered with theophylline (a
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
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
(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 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.
Tadalafil (10 mg and 20 mg) had no clinically significant effect on exposure (AUC) to
Aspirin
Tadalafil (10 mg and 20 mg) did not potentiate the increase in bleeding time caused by acetyl salicylic acid.
Antidiabetic medicinal products
Specific interaction studies with antidiabetic medicinal products were not conducted.
4.6 Fertility, pregnancy and lactation
Tadalafil Mylan 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 Mylan 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 Mylan 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 or benign prostatic hyperplasia 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
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
Frequency convention: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000), very rare (<1/10,000) and not known (cannot be estimated from the available data).
Very common | Common | Uncommon | Rare |
Immune system disorders | Hypersensitivity | Angioedema2 | |
|
| ||
Nervous system disorders | reactions |
| |
|
|

Headache | Dizziness | Stroke1 |
|
| (including haemorrhagic |
|
| events), |
|
| Syncope, |
|
| Transient ischaemic attacks1, |
|
| Migraine2, |
|
| Seizures2, |
|
| Transient amnesia |
Eye disorders
- Pregabalin mylan - Generics (UK) Limited
- Duloxetine mylan - Generics (UK) Limited
Prescription drugs listed. Manufacturer: "Generics (UK) Limited"
Blurred vision, | Visual field defect, |
Sensations described | Swelling of eyelids, |
as eye pain | Conjunctival hyperaemia, |
| |
| optic neuropathy (NAION)2, |
| Retinal vascular occlusion2 |
Ear and labyrinth disorders |
| ||
|
| Tinnitus | Sudden hearing loss |
|
|
|
|
Cardiac disorders1 |
|
|
|
|
| Tachycardia, | Myocardial infarction, |
|
| Palpitations | 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, |
|
|
|
| |
|
| reflux, |
|
Skin and subcutaneous | tissue disorders |
|
|
|
| Rash | Urticaria, |
|
|
| |
|
|
| Exfoliative dermatitis2 |
|
|
| Hyperhydrosis (sweating) |
Musculoskeletal and connective tissue 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 pain1, | Facial oedema2, |
|
| Peripheral oedema, | Sudden cardiac death1, 2 |
|
| Fatigue |
|
(1)Most of the patients had
(2)Postmarketing surveillance reported adverse reactions not observed in
(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, either for the treatment of erectile dysfunction or the treatment of benign prostatic hyperplasia, 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. 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 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 national reporting system listed in Appendix V.
4.9 Overdose
Single doses of up to 500 mg have been given to healthy subjects, and multiple daily doses up to 100 mg have been given to patients. 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.
5. 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
The effect of PDE5 inhibition on cGMP concentration in the corpus cavernosum is also observed in the smooth muscle of the prostate, the bladder and their vascular supply. The resulting vascular relaxation increases blood perfusion which may be the mechanism by which symptoms of benign prostatic hyperplasia are reduced. These vascular effects may be complemented by inhibition of bladder afferent nerve activity and smooth muscle relaxation of the prostate and bladder.
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 >
This selectivity for PDE5 over PDE3 is important because PDE3 is an enzyme involved in cardiac contractility. Additionally, tadalafil is approximately
Clinical efficacy and safety
Tadalafil administered to healthy subjects produced no significant difference compared to placebo in supine systolic and diastolic blood pressure (mean maximal decrease of 1.6/0.8 mm Hg, respectively), in standing systolic and diastolic blood pressure (mean maximal decrease of 0.2/4.6 mm Hg, 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
Three studies were conducted in men to assess the potential effect on spermatogenesis of tadalafil 10 mg (one
Erectile dysfunction
For tadalafil on demand, three clinical studies were conducted in 1054 patients in an
In a
For
various severities (mild, moderate, severe) and etiologies. In the two primary efficacy studies of general populations, the mean
217 patients who were
Benign prostatic hyperplasia
Tadalafil was studied in 4 clinical studies of 12 weeks duration enrolling over 1500 patients with signs and symptoms of benign prostatic hyperplasia. The improvement in the total international prostate symptom score with tadalafil 5 mg in the four studies were
and
One of these studies assessed improvements in erectile dysfunction and signs and symptoms of benign prostatic hyperplasia in patients with both conditions. The improvements in the erectile function domain of the international index of erectile function and the total international prostate symptom score in this study were 6.5 and
The maintenance of the effect was evaluated in an
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,
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
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, thus Tadalafil may be taken with or without food. The time of dosing (morning versus evening) had no clinically relevant effects on the rate and extent of absorption.
Distribution
The mean volume of distribution is approximately 63 l, indicating that tadalafil is distributed into tissues. At therapeutic concentrations, 94% of tadalafil in plasma is bound to proteins. Protein binding is not affected by impaired renal function.
Less than 0.0005% of the administered dose appeared in the semen of healthy subjects.
Biotransformation
Tadalafil is predominantly metabolised by the cytochrome P450 (CYP) 3A4 isoform. The major circulating metabolite is the methylcatechol glucuronide. This metabolite is at least
Elimination
The mean oral clearance for tadalafil is 2.5 l/h and the mean
Tadalafil pharmacokinetics in healthy subjects are linear with respect to time and dose. Over a dose range of 2.5 to 20 mg, exposure (AUC) increases proportionally with dose.
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
Haemodialysis contributes negligibly to tadalafil elimination.
Hepatic insufficiency
Tadalafil exposure (AUC) in subjects with mild and moderate 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
There was no evidence of teratogenicity, embryotoxicity or foetotoxicity in rats or mice that received up to 1000 mg/kg/day tadalafil. In a rat prenatal and postnatal development study, the no observed effect dose was
30 mg/kg/day. In the pregnant rat the AUC for calculated free drug at this dose was approximately 18 times the human AUC at a 20 mg 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 25 mg/kg/day (resulting in at least a
6. PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Tablet core:
Lactose, anhydrous
Poloxamer 188
Cellulose, microcrystalline (pH101)
Povidone
Croscarmellose sodium
Magnesium stearate
Sodium laurilsulfate
Silica, colloidal anhydrous
Lactose monohydrate
Hypromellose (E464)
Titanium dioxide (E171)
Iron oxide yellow (E172)
Triacetin
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
3 years
6.4 Special precautions for storage
This medicinal product does not require any special storage conditions.
6.5 Nature and contents of container
Pack sizes of 14, 28, 30, 56, 84 and 98 tablets.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal
Any unused medicinal product or waste material should be disposed of in accordance with local requirements
7. MARKETING AUTHORISATION HOLDER
Generics [UK] Limited
Station Close
Potters Bar
Hertfordshire
EN6 1TL
United Kingdom
8. MARKETING AUTHORISATION NUMBER(S)
EU/1/14/961/012
EU/1/14/961/013
EU/1/14/961/014
EU/1/14/961/015
EU/1/14/961/016
EU/1/14/961/017
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
Date of first authorisation: 21 November 2014
10. DATE OF REVISION OF THE TEXT
Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu.
1. NAME OF THE MEDICINAL PRODUCT
Tadalafil Mylan 10 mg
Tadalafil Mylan 20 mg
2. QUALITATIVE AND QUANTITATIVE COMPOSITION
Tadalafil Mylan 10 mg
Each tablet contains 10 mg tadalafil.
Excipient with known effect:
Each coated tablet contains 118.96 mg of lactose.
Tadalafil Mylan 20 mg
Each tablet contains 20 mg tadalafil.
Excipient with known effect:
Each coated tablet contains 237.92 mg of lactose.
For the full list of excipients, see section 6.1.
3. PHARMACEUTICAL FORM
Tadalafil Mylan 10 mg
A light yellow,
Tadalafil Mylan 20 mg
A light yellow,
4. 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 Mylan is not indicated for use by women.
4.2 Posology and method of administration
Posology
Adult men
In general, the recommended dose is 10 mg taken prior to anticipated sexual activity and with or without food.
In those patients in whom tadalafil 10 mg does not produce an adequate effect, 20 mg might be tried. It may be taken at least 30 minutes prior to sexual activity.
The maximum dose frequency is once per day.
Tadalafil 10 and 20 mg 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 5 mg taken once a day at approximately the same time of day. The dose may be decreased to 2.5 mg once a day based on individual tolerability.
The appropriateness of continued use of the daily regimen should be reassessed periodically.
Special populations
Elderly men
Dose adjustments are not required in elderly patients.
Men with renal impairment
Dose adjustments are not required in patients with mild to moderate renal impairment. For patients with severe renal impairment 10 mg is the maximum recommended dose.
Men with hepatic impairment
The recommended dose of tadalafil is 10 mg 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
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
Tadalafil Mylan is available as 2.5, 5, 10, and 20 mg
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
The following groups of patients with cardiovascular disease were not included in clinical trials and the use of tadalafil is therefore contraindicated:
-patients with myocardial infarction within the last 90 days,
-patients with unstable angina or angina occurring during sexual intercourse,
-patients with New York Heart Association Class 2 or greater heart failure in the last 6 months,
-patients with uncontrolled arrhythmias, hypotension (< 90/50 mm Hg), 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
The
4.4 Special warnings and precautions for use
Before treatment with Tadalafil Mylan
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
- Cialis - G04BE08
- Talmanco (tadalafil generics) - G04BE08
- Tadalafil lilly - G04BE08
- Tadalafil generics - G04BE08
- Adcirca (tadalafil lilly) - G04BE08
Prescription drugs listed. ATC Code: "G04BE08"
Cardiovascular
Serious cardiovascular events, including myocardial infarction, sudden cardiac death, unstable angina pectoris, ventricular arrhythmia, stroke, transient ischemic attacks, chest pain, palpitations and tachycardia, have been reported either post marketing and/or in clinical trials. Most of the patients in whom these events have been reported had
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 Mylan 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
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 Mylan in such combinations.
Lactose
Tadalafil Mylan contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or
4.5 Interaction with other medicinal products and other forms of interaction
Interaction studies were conducted with 10 mg and/or 20 mg tadalafil, as indicated below. With regard to those interaction studies where only the 10 mg tadalafil dose was used, clinically relevant interactions at higher doses cannot be completely ruled out.
Effects of other substances on tadalafil
Cytochrome P450 inhibitors
Tadalafil is principally metabolised by CYP3A4. A selective inhibitor of CYP3A4, ketoconazole (200 mg daily), increased tadalafil (10 mg) exposure (AUC)
Consequently the incidence of the adverse reactions listed in section 4.8 might be increased.
Transporters
The role of transporters (for example
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 phenobarbital, phenytoin and carbamazepine, may also decrease plasma concentrations of tadalafil.
Effects of tadalafil on other medicinal products
Nitrates
In clinical studies, tadalafil (5, 10 and 20 mg) was shown to augment the hypotensive effects of nitrates. 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 (2.5
The
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
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),
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
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
CYP1A2 substrates (e.g. theophylline)
When tadalafil 10 mg was administered with theophylline (a
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
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
(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 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.
Tadalafil (10 mg and 20 mg) had no clinically significant effect on exposure (AUC) to
Aspirin
Tadalafil (10 mg and 20 mg) did not potentiate the increase in bleeding time caused by acetyl salicylic acid.
Antidiabetic medicinal products
Specific interaction studies with antidiabetic medicinal products were not conducted.
4.6 Fertility, pregnancy and lactation
Tadalafil Mylan 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 Mylan 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 Mylan 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 or benign prostatic hyperplasia 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
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
Frequency convention: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000), very rare (<1/10,000) and not known (cannot be estimated from the available data).
Very common | Common | Uncommon | Rare |
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|
|
Immune system disorders |
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|
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| Hypersensitivity reactions | Angioedema2 |
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Nervous system disorders |
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| Headache | Dizziness | Stroke1 |
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| (including haemorrhagic |
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| events), |
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| Syncope, |
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| Transient ischaemic attacks1, |
|
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| Migraine2, |
|
|
| Seizures2, |
|
|
| Transient amnesia |
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|
|
|
Eye disorders |
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|
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| Blurred vision, | Visual field defect, |
|
| Sensations described as | Swelling of eyelids, |
|
| eye pain | Conjunctival hyperaemia, |
|
|
| |
|
|
| ischemic optic neuropathy |
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|
| (NAION)2, |
|
|
| Retinal vascular occlusion2 |
Ear and labyrinth disorders |
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| |
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| Tinnitus | Sudden hearing loss |
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|
|
|
Cardiac disorders1 |
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|
|
|
| Tachycardia, | Myocardial infarction, |
|
| Palpitations | Unstable angina pectoris2, |
|
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| Ventricular arrhythmia2 |
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|
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Vascular disorders |
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|
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|
|
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| Flushing | Hypotension3, |
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| Hypertension |
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Respiratory, thoracic and mediastinal disorders |
| ||
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|
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| Nasal | Dyspnoea, |
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| congestion | Epistaxis |
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Gastrointestinal disorders |
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| Dyspepsia, | Abdominal pain, |
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| Vomiting, Nausea, |
|
|
|
| |
|
| reflux, |
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Skin and subcutaneous | tissue disorders |
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| Rash | Urticaria, |
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| |
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| Exfoliative dermatitis2, |
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| Hyperhydrosis (sweating) |
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|
|
Musculoskeletal and connective tissue disorders |
| ||
| Back pain, |
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| Myalgia, |
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| Pain in |
|
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| extremity |
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Renal and urinary disorders |
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| |
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| Haematuria |
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Reproductive system and | breast disorders |
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|
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| Prolonged erections | Priapism ,Penile haemorrhage, |
|
|
| Haematospermia |
|
|
|
|
General disorders and | administration site | conditions |
|

Chest pain1, Peripheral | Facial oedema2, |
oedema, Fatigue | Sudden cardiac death1, 2 |
(1)Most of the patients had
(2)Postmarketing surveillance reported adverse reactions not observed in
(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, either for the treatment of erectile dysfunction or the treatment of benign prostatic hyperplasia, 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. 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 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 national reporting system listed in Appendix V.
4.9 Overdose
Single doses of up to 500 mg have been given to healthy subjects, and multiple daily doses up to 100 mg have been given to patients. 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.
5. 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
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 >
This selectivity for PDE5 over PDE3 is important because PDE3 is an enzyme involved in cardiac contractility. Additionally, tadalafil is approximately
Clinical efficacy and safety
Three clinical studies were conducted in 1054 patients in an
Tadalafil administered to healthy subjects produced no significant difference compared to placebo in supine systolic and diastolic blood pressure (mean maximal decrease of 1.6/0.8 mm Hg, respectively), in standing systolic and diastolic blood pressure (mean maximal decrease of 0.2/4.6 mm Hg, 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 10 mg (one
Tadalafil at doses of 2 to 100 mg has been evaluated in 16 clinical studies involving 3250 patients, including patients with erectile dysfunction of various severities (mild, moderate, severe), etiologies, ages (range
In a
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,
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
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, thus tadalafil may be taken with or without food. The time of dosing (morning versus evening) had no clinically relevant effects on the rate and extent of absorption.
Distribution
The mean volume of distribution is approximately 63 l, indicating that tadalafil is distributed into tissues. At therapeutic concentrations, 94% of tadalafil in plasma is bound to proteins. Protein binding is not affected by impaired renal function.
Less than 0.0005% of the administered dose appeared in the semen of healthy subjects.
Biotransformation
Tadalafil is predominantly metabolised by the cytochrome P450 (CYP) 3A4 isoform. The major circulating metabolite is the methylcatechol glucuronide. This metabolite is at least
Elimination
The mean oral clearance for tadalafil is 2.5 l/h and the mean
Tadalafil pharmacokinetics in healthy subjects is linear with respect to time and dose. Over a dose range of 2.5 to 20 mg, exposure (AUC) increases proportionally with dose.
Pharmacokinetics determined with a population approach in patients with erectile dysfunction is 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
Haemodialysis contributes negligibly to tadalafil elimination.
Hepatic insufficiency
Tadalafil exposure (AUC) in subjects with mild and moderate hepatic impairment
physician. There are no available data about the administration of doses higher than 10 mg 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
There was no evidence of teratogenicity, embryotoxicity or foetotoxicity in rats or mice that received up to 1000 mg/kg/day tadalafil. In a rat prenatal and postnatal development study, the no observed effect dose was 30 mg/kg/day. In the pregnant rat the AUC for calculated free drug at this dose was approximately 18 times the human AUC at a 20 mg 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 25 mg/kg/day (resulting in at least a
6. PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Tablet core:
Lactose, anhydrous
Poloxamer 188
Cellulose, microcrystalline (pH101)
Povidone
Croscarmellose sodium
Magnesium stearate
Sodium laurilsulfate
Silica, colloidal anhydrous
Lactose monohydrate
Hypromellose (E464)
Titanium dioxide (E171)
Iron oxide yellow (E172)
Triacetin
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
3 years
6.4 Special precautions for storage
This medicinal product does not require any special storage conditions.
6.5 Nature and contents of container
Tadalafil Mylan 10 mg
Pack sizes of 4, 12 and 24 tablets.
Tadalafil Mylan 20 mg
Pack sizes of 2, 4, 8,12 and 24 tablets
Not all pack sizes may be marketed.
6.6 Special precautions for disposal
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
.
7. MARKETING AUTHORISATION HOLDER
Generics [UK] Limited
Station Close
Potters Bar
Hertfordshire
EN6 1TL
United Kingdom
8. MARKETING AUTHORISATION NUMBER(S)
Tadalafil Mylan 10 mg
EU/1/14/961/001
EU/1/14/961/010
EU/1/14/961/011
Tadalafil Mylan 20 mg
EU/1/14/961/002
EU/1/14/961/003
EU/1/14/961/004
EU/1/14/961/005
EU/1/14/961/006
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
- Terrosa
- Velphoro
- Comtess
- Enurev breezhaler
- Actelsar hct
- Ebilfumin
Prescription drugs listed:
Date of first authorisation: 21 November 2014
10. DATE OF REVISION OF THE TEXT
Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu.
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