SilaMEN

Tadalafil

Film-coated tablets

Dosage 5 mg: golden yellow round biconvex film-coated tablets scored on one side to split the tablet in half.
Dosage 20 mg: golden yellow oval biconvex film-coated tablets scored on one side to split the tablet in half.

Each tablet contains:
Active substance: tadalafil 5 mg or 20 mg;
Auxiliary substances: lactose monohydrate, croscarmellose sodium, hydroxypropylcellulose, Kolliphor P188 micro poloxamer, sodium lauryl sulfate, magnesium stearate, microcrystalline cellulose;
Coating composition: hydroxypropyl methylcellulose, polyethylene glycol (macrogol), potassium aluminum silicate (E 555), titanium dioxide (E171), iron oxide red (E172).

Medications for treatment of urological diseases. Urologicals, medications used in erectile dysfunction.

G04BE08

Tadalafil is a potent and selective inhibitor of phosphodiesterase type 5 (PDE5) – cyclic guanosine monophosphate (cGMP). When sexual stimulation causes the local release of nitric oxide, inhibition of PDE5 by tadalafil produces increased levels of cGMP in the corpus cavernosum. This results in smooth muscle relaxation and inflow of blood into the penile tissues, thereby producing an erection. Tadalafil has no effect in the treatment of erectile dysfunction in the absence of sexual stimulation.

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 (BPH) are reduced. These vascular effects may be complemented by inhibition of bladder afferent nerve activity and smooth muscle relaxation of the prostate and bladder.

Studies in vitro have shown that tadalafil is a selective inhibitor of PDE5. It 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 and demonstrated improvement in erectile function and the ability to have successful sexual intercourse up to 36 hours following dosing, as well as manifestation of the effect 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 1.6/0.8 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. 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.

Treatment of erectile dysfunction in adult males.
For the medication to be effective sexual stimulation is required.
Treatment of the signs and symptoms of benign prostatic hyperplasia in adult males (dosage 5 mg).
SilaMEN is not indicated for use by women.

Tablets are taken orally with or without food.

Treatment of erectile dysfunction in adult males
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 should 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.
Drinking alcohol can affect your ability to achieve an erection, so excessive alcohol consumption should be avoided while taking SilaMEN.

Treatment of 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.

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.
Once-a-day dosing of 2.5 or 5 mg tadalafil both for the treatment of erectile dysfunction or benign prostatic hyperplasia is not recommended in patients with severe renal impairment.

Men with hepatic impairment
For the treatment of erectile dysfunction, the recommended dose of the medication is 10 mg taken prior to anticipated sexual activity and with or without food. There is limited clinical data on the safety of SilaMEN 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 10 mg of tadalafil to patients with hepatic impairment.

Once-a-day dosing both for the treatment of erectile dysfunction and benign prostatic hyperplasia has not been evaluated in patients with hepatic impairment; therefore, so if SilaMEN is prescribed, a careful individual benefit/risk evaluation should be undertaken by the physician.

Men with diabetes mellitus
Dose adjustments are not required.

Children and adolescents
The medication is not indicated for use in children. The safety and efficacy of tadalafil in children and adolescents (under 18 years of age) have not been established.

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 the medication. 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.

Concurrent reactions are presented by classes of organ systems and occurrence rate: very common (≥1/10), common (≥1/100, but <1/10), uncommon (≥1/1000, but <1/100), rare (≥1/10000, but <1/1000), very rare (<1/10000). The following adverse reactions are possible when using tadalafil:

Immune system disorders
Uncommon: hypersensitivity reactions,
Rare: angioedema².

Nervous system disorders
Common: headache;
Uncommon: dizziness;
Rare: stroke¹ (including haemorrhagic events), syncope, transient ischaemic attacks¹, migraine², seizures², transient amnesia.

Eye disorders
Uncommon: blurred vision, sensations described as eye pain;
Rare: visual field defect, swelling of eyelids, conjunctival hyperaemia, non-arteritic anterior ischaemic optic neuropathy (NAION)², retinal vascular occlusion².

Ear and labyrinth disorders
Uncommon: tinnitus;
Rare: sudden hearing loss.

Cardiac disorders¹
Uncommon: tachycardia, palpitations;
Rare: myocardial infarction, unstable angina pectoris², ventricular arrhythmia².

Vascular disorders
Common: flushing;
Uncommon: hypotension³, hypertension.

Respiratory, thoracic and mediastinal disorders
Common: nasal congestion;
Uncommon: dyspnoea, epistaxis.

Gastrointestinal disorders
Common: dyspepsia, gastro-oesophageal reflux;
Uncommon: abdominal pain.

Skin and subcutaneous tissue disorders
Uncommon: rash, hyperhydrosis (sweating);
Rare: urticaria, Stevens-Johnson syndrome², exfoliative dermatitis².

Musculoskeletal and connective tissue disorders
Common: back pain, myalgia, and pain in extremity.

Renal and urinary disorders
Uncommon: haematuria.

Reproductive system and breast disorders
Uncommon: penile haemorrhage, haematospermia;
Rare: prolonged erections, priapism².

General disorders and administration site conditions
Uncommon: chest pain¹;
Rare: facial oedema², sudden cardiac death^1,2.

¹ Most of the patients with such adverse reactions had pre-existing cardiovascular risk factors.
² Postmarketing surveillance reported adverse reactions not observed in placebo-controlled clinical trials.
³ More commonly reported when tadalafil is given together with 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.

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 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.

If any of the undesirable effects listed in the instructions worsen, or you notice any other undesirable effects not listed in the leaflet, inform your healthcare provider about it.

• Hypersensitivity to tadalafil or to any other component of SilaMEN.
• 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 NO/cGMP pathway. Therefore, administration of tadalafil to patients who are using any form of organic nitrate is contraindicated.
• 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.
• Tadalafil is contraindicated in the following groups of patients with cardiovascular disease:
  • 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 non-arteritic anterior ischaemic optic neuropathy (NAION), regardless of whether this episode was in connection or not with previous PDE5 inhibitor exposure.
• 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.

If taking a larger dose than prescribed by your doctor, immediately contact specialists to provide timely medical care!
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.

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 medications on tadalafil
Cytochrome P450 inhibitors
Tadalafil is principally metabolised by CYP3A4. A selective inhibitor of CYP3A4, ketoconazole (200 mg daily), increased tadalafil (10 mg) exposure (AUC) 2-fold and C_max by 15%, relative to the AUC and C_max values for tadalafil alone. Ketoconazole (400 mg daily) increased tadalafil (20 mg) exposure (AUC) 4-fold and C_max by 22%. Ritonavir, a protease inhibitor (200 mg twice daily), which is an inhibitor of CYP3A4, CYP2C9, CYP2C19, and CYP2D6, increased tadalafil (20 mg) exposure (AUC) 2-fold with no change in C_max. Although specific interactions have not been studied, other protease inhibitors, such as saquinavir, and other CYP3A4 inhibitors, such as erythromycin, clarithromycin, itraconazole, and grapefruit juice, should be co-administered with caution, as they would be expected to increase plasma concentrations of tadalafil. Consequently, the incidence of the adverse reactions 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 (10 mg). It may be assumed that this reduced exposure can be anticipated to decrease the efficacy of tadalafil. 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. Thus, in a patient prescribed any dose of tadalafil (2.5 mg – 20 mg), where nitrate administration is deemed medically necessary in a life-threatening situation, at least 48 hours should have elapsed after the last dose of SilaMEN 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 8 mg daily) and tadalafil (5 mg daily dose and 20 mg as a single dose) increases the blood pressure-lowering effect of this alpha-blocker in a significant manner. This effect lasts at least twelve hours and may be symptomatic, including syncope. This combination is not recommended for use.

In interaction studies performed in a limited number of healthy volunteers, these effects were not reported with alfuzosin or tamsulosin. Caution should be exercised when using tadalafil in patients treated with any alpha-blockers, and notably in the elderly. Treatments should be initiated at minimal dosage and progressively adjusted.

In clinical pharmacology studies, the potential for tadalafil to augment the hypotensive effects of antihypertensive medicinal products was examined. Major classes of antihypertensive medicinal products were studied, including calcium-channel blockers (amlodipine), angiotensin converting enzyme (ACE) inhibitors (enalapril), beta-adrenergic receptor blockers (metoprolol), thiazide diuretics (bendrofluazide), and angiotensin II receptor blockers (various types and doses, alone or in combination with thiazides, calcium-channel blockers, beta-blockers, and/or alpha-blockers). Tadalafil (10 mg, except for studies with angiotensin II receptor blockers and amlodipine in which a 20 mg dose was applied) had no clinically significant interaction with any of these classes. In another clinical pharmacology study, tadalafil (20 mg) was studied in combination with up to 4 classes of antihypertensives. In patients taking multiple antihypertensives, the ambulatory-blood-pressure changes appeared to relate to the degree of blood pressure control. In this regard, patients whose blood pressure was well controlled, the reduction was minimal and similar to that seen in healthy subjects. In patients whose blood pressure was not controlled, the reduction was greater, although this reduction was not associated with hypotensive symptoms in the majority of patients. In patients receiving concomitant antihypertensive medicinal products, tadalafil 20 mg may induce a blood pressure decrease, which (with the exception of alpha-blockers) 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.

5-alpha reductase inhibitors
In a clinical trial that compared tadalafil 5 mg co-administered with finasteride 5 mg to placebo plus finasteride 5 mg in the relief of 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 10 mg was administered with theophylline (a non-selective phosphodiesterase inhibitor) in a clinical pharmacology study, there was no pharmacokinetic interaction. The only pharmacodynamic effect was a small (3.5 bpm) increase in heart rate. Although this effect is minor and was of no clinical significance in this study, it should be considered when co-administering tadalafil and theophylline.

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 (10 mg or 20 mg). In addition, no changes in tadalafil concentrations were seen 3 hours after co-administration with alcohol. Alcohol was administered in a manner to maximize the rate of alcohol absorption (overnight fast with no food until 2 hours after alcohol). Tadalafil (20 mg) did not augment the mean blood pressure decrease produced by alcohol (0.7 g/kg or approximately 180 ml of 40% alcohol in an 80 kg male) but, in some subjects, postural dizziness and orthostatic hypotension were observed. When tadalafil was administered with lower doses of alcohol (0.6 g/kg), hypotension was not observed and dizziness occurred with similar frequency to alcohol alone. The effect of alcohol on cognitive function was not augmented by tadalafil (10 mg).

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 (10 mg and 20 mg) had no clinically significant effect on exposure (AUC) to S-warfarin or R-warfarin (CYP2C9 substrate), nor did tadalafil affect changes in prothrombin time induced by warfarin.

Aspirin
Tadalafil (10 mg and 20 mg) 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.

Inform your doctor about all medications you are taking. Consult your doctor before you start taking any medication during treatment with SilaMEN.

Before treatment
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 and as such potentiates the hypotensive effect of nitrates.

Prior to benign prostatic hyperplasia treatment with tadalafil, a thorough examination of patients for cardiovascular diseases, as well as to exclude the presence of prostate carcinoma, should be carried out.

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 receiving concomitant antihypertensive medicinal products, tadalafil may induce a blood pressure decrease. When initiating daily treatment with tadalafil, appropriate considerations should be given to a possible dose adjustment of the antihypertensive therapy.
In patients who are taking alpha¹ blockers, concomitant administration of SilaMEN may lead to symptomatic hypotension in some patients. 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. The patient should be advised that in case of sudden visual defect, he should stop taking tadalafil and consult a physician immediately.

Renal and hepatic impairment
Due to increased tadalafil exposure (AUC), limited clinical experience and the lack of ability to influence clearance by dialysis, once-a-day dosing of SilaMEN is not recommended in patients with severe renal impairment.

There is limited clinical data on the safety of single-dose administration of tadalafil in patients with severe hepatic insufficiency (Child-Pugh Class C). Once-a-day administration of tadalafil has not been evaluated in patients with hepatic insufficiency. If tadalafil is prescribed, a careful individual benefit/risk evaluation should be undertaken by the 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.

SilaMEN 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).

Concomitant use with CYP3A4 inhibitors
Caution should be exercised when prescribing SilaMEN 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.

Combined use with other medications for treatment of 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 SilaMEN in such combinations.

Special information on auxiliary substances
SilaMEN contains lactose. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take SilaMEN.

If you have one of the diseases or conditions listed above, be sure to consult your doctor before taking SilaMEN.

SilaMEN is not indicated for use by women.

Fertility
Two subsequent clinical studies suggest that this effect is unlikely in humans, although a decrease in sperm concentration was seen in some men.

SilaMEN 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 SilaMEN before driving or using machines.

Film-coated tablets 5 mg.
15 tablets in a blister made of three-layer film (PVC/PE/PVDC) and flexible packing based on aluminum foil. 1 blister with a patient information leaflet, packed in a carton.
Film-coated tablets 20 mg.
4 tablets in a blister made of three-layer film (PVC/PE/PVDC) and flexible packing based on aluminum foil. 1 blister with a patient information leaflet, packed in a carton.

Do not store above 25°C. Keep away from children.

2 years. Do not use after the expiration date indicated on the package.

State enterprise ACADEMPHARM
220141, 5/3 Kuprevicha Street, Minsk, Belarus
Phone / Fax +375 17 268 63 64
production@academpharm.by
To report adverse reactions use the electronic application form on the manufacturer’s website: https://academpharm.by/en