Active ingredients: Tadalafil
CIALIS 2.5 mg film-coated tablets
Cialis package inserts are available for packs:- CIALIS 2.5 mg film-coated tablets
- CIALIS 5 mg film-coated tablets
- CIALIS 10 mg film-coated tablets
- CIALIS 20 mg film-coated tablets
Indications Why is Cialis used? What is it for?
CIALIS is a treatment for adult men with erectile dysfunction. This condition occurs when a man fails to achieve or maintain an erection suitable for intercourse. CIALIS has been shown to significantly improve the ability to obtain an erection suitable for intercourse.
CIALIS contains the active substance tadalafil which belongs to a class of medicines called phosphodiesterase type 5 inhibitors. After sexual stimulation CIALIS helps to relax the blood vessels in the penis, allowing blood to flow to the penis. The result is better erectile function. CIALIS will not help you if you do not have erectile dysfunction.
It is important to note that CIALIS has no effect unless there is sexual stimulation. You and your partner will need to engage in foreplay, as you would if you were not taking erectile dysfunction medication.
Contraindications When Cialis should not be used
Do not take CIALIS if:
- you are allergic to tadalafil or any of the other ingredients of this medicine (listed in section 6).
- are taking any form of organic nitrate or nitric oxide donors, such as amyl nitrite. This is a group of medicines ("nitrates") used to treat angina pectoris (or "chest pain"). CIALIS has been shown to increase the effect of these medicines. If you are taking any form of nitrate or are unsure, please tell your doctor.
- have severe heart disease or have recently had a heart attack within the past 90 days.
- had a stroke recently, in the past 6 months.
- have low blood pressure or uncontrolled high blood pressure.
- in the past she had loss of vision due to non-arteritic anterior ischemic optic neuropathy (NAION), a condition described as "icuts of the" eye.
Precautions for use What you need to know before taking Cialis
Talk to your doctor before taking CIALIS.
Be aware that sexual activity carries a potential risk for patients with heart disease, because it puts extra strain on the heart. If you have a heart problem, tell your doctor.
Before taking the tablets, tell your doctor if you have:
- l "sickle cell anemia (a" red blood cell abnormality).
- multiple myeloma (malignant tumor of the bone marrow).
- leukemia (malignant tumor of the blood cells).
- any deformity of the penis.
- a severe liver problem.
- a severe kidney problem.
It is not known whether CIALIS is effective in patients who have undergone:
- pelvic surgery
- removal of all or part of the prostate gland where the nerves of the prostate have been cut (radical prostatectomy without preservation of the vascular-nerve bundles).
If you have a sudden decrease or loss of vision, stop taking CIALIS and contact your doctor immediately.
CIALIS is not intended for use by women.
Children and adolescents
CIALIS is not intended for use by children and adolescents under the age of 18.
Interactions What drugs or foods can change the effect of Cialis
Tell your doctor if you are taking, have recently taken or might take any other medicines.
Do not take CIALIS if you are already taking nitrates.
Some medicines can be affected by CIALIS or they can themselves affect the way CIALIS works. Tell your doctor or pharmacist if you are already taking:
- an alpha blocker (used to treat high blood pressure or urinary problems associated with benign prostatic hyperplasia).
- other medicines to treat high blood pressure.
- a 5 alpha-reductase enzyme inhibitor (used to treat benign prostatic hyperplasia).
- medicines such as ketoconazole tablets (to treat fungal infections) and protease inhibitors to treat AIDS or HIV infection.
- phenobarbital, phenytoin and carbamazepine (anticonvulsant medicines).
- rifampicin, erythromycin, clarithromycin or itraconazole.
- other treatments for erectile dysfunction.
CIALIS with drinks and alcohol
Information on the effects of alcohol can be found in section 3. Grapefruit juice can affect the way CIALIS works and should be taken with caution. Ask your doctor for more information.
Warnings It is important to know that:
Fertility
In treated dogs there was a reduction in sperm development in the testes. A reduction in sperm count has been observed in some men. These effects are unlikely to cause a lack of fertility.
Driving and using machines
Some men taking CIALIS during clinical trials have reported dizziness. Check carefully how you react to the tablets before driving or using machines.
CIALIS contains lactose:
If you have an intolerance to some sugars, contact your doctor before taking this medicine.
Dose, Method and Time of Administration How to use Cialis: Posology
Always take this medicine exactly as your doctor has told you. If in doubt, consult your doctor or pharmacist.
CIALIS tablets are for oral use and for men only. Swallow the tablet whole with water. The tablets can be taken regardless of food intake.
The recommended dose is one 5 mg tablet to be taken once a day at approximately the same time of day. Your doctor may adjust the dose to 2.5 mg based on your response to CIALIS. This dose will be given to you with a 2.5 mg tablet.
Do not take CIALIS more than once a day.
Once-a-day administration of CIALIS may be helpful to men who plan to have sexual activity two or more times a week.
When taken once a day, CIALIS allows you to have an "erection, if there is sexual stimulation, at any time of the day within 24 hours. It is important to note that CIALIS does not work unless there is" sexual stimulation. . You and your partner will need to engage in foreplay as you would if they were not taking an erectile dysfunction medication.
Drinking alcoholic beverages can interfere with your ability to get an erection and can temporarily cause your blood pressure to drop. If you have taken or are planning to take CIALIS, avoid excessive alcohol intake (blood alcohol level 0.08% or higher) as this may increase the risk of dizziness when standing up. .
Overdose What to do if you have taken too much Cialis
If you take more CIALIS than you should
Contact your doctor. The side effects described in section 4 may occur.
If you forget to take CIALIS
Take your dose as soon as you remember but do not take a double dose to make up for a forgotten tablet. You must not take CIALIS more than once a day.
If you have any further questions on the use of this medicine, ask your doctor or pharmacist.
Side Effects What are the side effects of Cialis
Like all medicines, this medicine can cause side effects, although not everybody gets them. These effects are usually mild to moderate in severity.
If you experience any of the following side effects, stop using the medicine and seek medical help immediately:
- allergic reactions, including skin rashes (frequency uncommon).
- chest pain - do not use nitrates but seek immediate medical attention (frequency uncommon).
- Prolonged and possibly painful erection after taking CIALIS (frequency rare). If you have an erection of this type that lasts for more than 4 hours in a row, you should contact a doctor immediately.
- sudden loss of vision (frequency rare).
Other side effects have been reported:
Common (observed in 1 to 10 of every 100 patients)
headache, back pain, muscle aches, pain in the arms and legs, flushing of the face, nasal congestion, digestive upset and reflux.
Uncommon (observed in 1 to 10 in every 1,000 patients)
dizziness, stomach pain, blurred vision, sore eyes, increased sweating, difficulty breathing, penile bleeding, blood in semen and / or urine, palpitations, fast heartbeat, high blood pressure, low blood pressure , nosebleed and ringing in the ears.
Rare (observed in 1 to 10 patients in 10,000)
fainting, seizures and transient memory loss, swollen eyelids, red eyes, sudden decrease or loss of hearing and hives (itchy red patches on the skin surface).
Heart attacks and strokes have been reported rarely in men taking CIALIS. Most of these people had heart problems even before using the medicine.
There have been rare reports of partial, temporary or permanent decrease or loss of vision in one or both eyes.
Some additional rare side effects that were not seen in clinical trials have been reported in men taking CIALIS. These include:
migraine, swelling of the face, severe allergic reaction causing swelling of the face and throat, severe skin reactions, certain disorders that change the blood circulation to the eyes, irregular heartbeat, angina and sudden cardiac death.
Side effects of dizziness and diarrhea have been reported more frequently in men over 75 years of age taking CIALIS.
If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet.
Expiry and Retention
Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date which is stated on the carton and blister after EXP. The expiry date refers to the last day of that month.
Store in the original package in order to protect from moisture. Do not store above 30 ° C.
Do not throw any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. This will help protect the environment.
Source Package Leaflet: AIFA (Italian Medicines Agency). Content published in January 2016. The information present may not be up-to-date.
To have access to the most up-to-date version, it is advisable to access the AIFA (Italian Medicines Agency) website. Disclaimer and useful information.
01.0 NAME OF THE MEDICINAL PRODUCT
CIALIS 2.5 MG
02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each tablet contains 2.5 mg of tadalafil.
Excipient (s) with known effect:
each film-coated tablet contains 87 mg of lactose (as monohydrate).
For the full list of excipients, see section 6.1.
03.0 PHARMACEUTICAL FORM
Film-coated tablet (tablet).
Light yellow-orange, almond-shaped tablets, marked "C 2 ½" on one side.
04.0 CLINICAL INFORMATION
04.1 Therapeutic indications
Treatment of erectile dysfunction in adult men.
Sexual stimulation is required for tadalafil to be effective.
The use of CIALIS in women is not indicated.
04.2 Posology and method of administration
Dosage
Adult men
In general, the recommended dose is 10 mg taken before anticipated sexual activity and regardless of meals.
In those patients in whom a 10 mg dose of tadalafil does not produce an adequate effect, a 20 mg dose may be tried. The medicine can be taken at least 30 minutes before sexual activity.
The maximum frequency of administration is once a day.
Tadalafil 10 mg and 20 mg is intended for use prior to anticipated sexual activity and is not recommended for continuous daily use.
In patients anticipating frequent use of CIALIS (e.g., at least twice weekly) a once daily regimen with the lowest doses of CIALIS may be considered suitable, based on patient choice and physician judgment. .
In these patients the recommended dose is 5 mg taken once daily at approximately the same time of day. The dose may be decreased to 2.5 mg once daily based on individual tolerability.
The appropriateness of continued use of the daily dosing schedule should be reassessed periodically.
Special populations
Older men
No dose adjustments are required in elderly patients.
Men with renal insufficiency
No dose adjustments are required in patients with mild to moderate renal impairment.
For patients with severe renal insufficiency the maximum recommended dose is 10 mg. Once-a-day dosing of tadalafil is not recommended in patients with severe renal impairment. (see sections 4.4 and 5.2).
Men with liver failure
The recommended dose of CIALIS is 10 mg to be taken before anticipated sexual activity and regardless of meals. There is limited clinical data on the safety of CIALIS in patients with severe hepatic impairment (Child-Pugh class C); if prescribed, a careful individual benefit-risk assessment should be made by the prescribing physician. There are no data available regarding the administration of tadalafil at doses greater than 10 mg to patients with hepatic insufficiency. once daily has not been evaluated in patients with hepatic insufficiency; therefore, if prescribed, a "careful case-by-case evaluation of the benefit-risk ratio by the prescribing physician should be performed. (see sections 4.4 and 5.2).
Diabetic men
Dosage adjustments are not required in diabetic patients.
Pediatric population
There is no indication for a specific use of CIALIS in the pediatric population in relation to the treatment of erectile dysfunction.
Method of administration
CIALIS is available as 2.5 mg, 5 mg, 10 mg and 20 mg film-coated tablets for oral use.
04.3 Contraindications
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
In clinical studies, tadalafil was shown to increase the hypotensive effects of nitrates. This increase is believed to result from the combined effects of nitrates and tadalafil on the nitric oxide / cGMP pathway. Therefore, the administration of CIALIS to patients who are taking any form of organic nitrate is contraindicated. (see section 4.5).
CIALIS should not be used in men with heart disease for whom sexual activity is not recommended. Physicians should consider the potential cardiac risk associated with sexual activity in patients with pre-existing cardiovascular disease.
The following groups of patients with cardiovascular disease were not included in clinical studies and the use of tadalafil is therefore contraindicated:
• patients who have had myocardial infarction in the past 90 days,
• patients with unstable angina or who have had episodes of angina during sexual intercourse,
• patients who have had Class 2 or greater heart failure according to the New York Heart Association classification within the past 6 months,
• patients with uncontrolled arrhythmias, hypotension (uncontrolled hypertension,
• patients who have had a stroke in the past 6 months.
CIALIS is contraindicated in patients who have lost vision in one eye due to non-arteritic anterior ischemic optic neuropathy (NAION), regardless of whether this event was related to previous use of a PDE5 inhibitor (see section 4.4). ).
04.4 Special warnings and appropriate precautions for use
Before treatment with CIALIS
Before considering drug treatment, a medical history and physical examination should be done in order to diagnose erectile dysfunction and determine the underlying causes of the disease.
Because there is a degree of cardiac risk associated with sexual activity, physicians will need to evaluate the cardiovascular condition of patients before initiating any treatment for erectile dysfunction. Tadalafil has vasodilatory properties that result in mild and transient decreases in blood pressure (see section 5.1) and therefore potentiates the hypotensive effect of nitrates (see section 4.3).
Evaluation of erectile dysfunction should include a determination of the potential underlying causes of the condition and the identification of appropriate treatment following an appropriate medical evaluation. It is not known whether CIALIS is effective in patients who have undergone pelvic surgery or non-conserving radical prostatectomy.
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 post-marketing and / or in clinical trials. Most 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 directly related to these risk factors, to CIALIS, to sexual activity, or to a combination of these or other factors.
In patients receiving concomitant antihypertensive medicinal products, tadalafil may induce a reduction in blood pressure. When daily treatment with tadalafil is initiated, appropriate clinical evaluation should be performed for a possible dose adjustment of antihypertensive therapy.
In patients taking alpha1-blockers, co-administration of CIALIS may induce symptomatic hypotension in some patients (see section 4.5). The combination of tadalafil and doxazosin is not recommended.
View
Visual disturbances and cases of NAION have been reported in association with the use of CIALIS and other PDE5 inhibitors. The patient should be advised that in the event of sudden visual impairment, he should stop taking CIALIS and consult a physician immediately ( see section 4.3).
Renal and hepatic insufficiency
Due to the increased exposure (AUC) to tadalafil, limited clinical experience and the lack of ability to affect clearance by dialysis, once-daily administration of CIALIS is not recommended in patients with severe renal impairment.
There is limited clinical data on the safety of CIALIS given as a single dose in patients with severe hepatic impairment (Child-Pugh Class C). Once daily dosing has not been evaluated in patients with hepatic insufficiency. If CIALIS is prescribed, a "careful case-by-case assessment of the benefit-risk ratio should be performed by the prescribing physician.
Priapism and anatomical deformations of the penis
Patients who have erections lasting 4 hours or more should be advised to seek immediate medical assistance. If priapism is not treated immediately, it can cause damage to penile tissue and a permanent loss of potency.
CIALIS should be used with caution in patients with anatomical deformations of the penis (eg angulation, cavernous fibrosis or Peyronie's disease) or in patients with conditions that may predispose to priapism (such as sickle cell anemia, multiple myeloma or leukemia) .
Use with CYP3A4 inhibitors
Caution is advised when prescribing CIALIS to patients who are using potent CYP3A4 inhibitors (ritonavir, saquinavir, ketoconazole, itraconazole and erythromycin) as increased exposure (AUC) to tadalafil has been observed when the medicinal products are given in combination (see paragraph 4.5).
CIALIS and other treatments for erectile dysfunction
The safety and efficacy of combining CIALIS with other PDE5 inhibitors or other treatments for erectile dysfunction have not been studied. Patients should be advised not to take CIALIS in combination with such medicinal products.
Lactose
CIALIS contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
04.5 Interactions with other medicinal products and other forms of interaction
As noted below, interaction studies were conducted with 10 mg and / or 20 mg of tadalafil.
For those interaction studies where only the 10 mg dose of tadalafil was used, clinically significant interactions cannot be completely excluded at higher doses.
Effects of other substances on tadalafil
Inhibitors of cytochrome P450
Tadalafil is mainly metabolised by CYP3A4. A selective inhibitor of CYP3A4, ketoconazole (200 mg daily), increased tadalafil (10 mg) exposure (AUC) 2-fold and Cmax (10 mg) by 15% relative to tadalafil AUC and Cmax values from alone. Ketoconazole (400 mg daily) increased tadalafil (20 mg) exposure (AUC) 4-fold and Cmax by 22%. A protease inhibitor, ritonavir (200 mg twice daily) which is a inhibitor of CYP3A4, CYP2C9, CYP2C19 and CYP2D6, increased the exposure (AUC) 2-fold and did not change the Cmax of tadalafil (20 mg). 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 administered together with caution as it is expected that increase the plasma concentrations of tadalafil (see section 4.4). Consequently, the incidence of adverse reactions listed in section 4.8 may be increased.
Conveyors
The role of transporters (e.g. p-glycoprotein) in the distribution of tadalafil is unknown.
There is therefore the possibility of drug interaction mediated by the inhibition of transporters.
Inducers of cytochrome P450
A CYP3A4 inducer, rifampicin, reduced the AUC of tadalafil by 88% compared to the AUC values of tadalafil alone (10 mg). This reduced exposure may predict a reduction in the efficacy of tadalafil; the degree of reduction in efficacy is not known. Other inducers of CYP3A4, such as phenobarbital, phenytoin and carbamazepine, may also reduce the plasma concentrations of tadalafil.
Effects of tadalafil on other medicinal products
Nitrates
In clinical studies, tadalafil (5, 10 and 20 mg) was shown to increase the hypotensive effects of nitrates. Therefore, administration of CIALIS to patients who are taking any form of organic nitrate is contraindicated (see section 4.3). Based on the results of a clinical study in which 150 subjects received a daily dose of 20 mg of tadalafil for 7 days and 0.4 mg of sublingual nitroglycerin at different times, this interaction lasted for more than 24 hours and was not most detected when 48 hours had elapsed after the last dose of tadalafil. Therefore, in a patient who has been prescribed any dosage of CIALIS (2.5 mg-20 mg), and in whom nitrate administration is considered necessary by a medical point of view for a life-threatening situation, at least 48 hours should elapse after the last dose of CIALIS before nitrate administration is considered. In such circumstances, nitrates should only be administered under close medical supervision with appropriate monitoring of the haemodynamic situation.
Antihypertensives (including calcium channel blockers)
Co-administration of doxazosin (4 and 8 mg daily) and tadalafil (5 mg daily and 20 mg single dose) significantly increases the hypotensive effect of alpha-blockers. This effect lasts for at least twelve hours and may be associated with symptoms including syncope, therefore this combination is not recommended (see section 4.4).
These effects were not reported in interaction studies with alfuzosin and tamsulosin in a limited number of healthy volunteers. However, caution is recommended when tadalafil is used in patients treated with any alpha blocker and particularly in elderly patients. they should be started at the lowest dosage and progressively adjusted.
The potential of tadalafil to increase the hypotensive effects of antihypertensive medicinal products was evaluated in clinical pharmacological studies. Major classes of antihypertensive drugs were studied, including calcium channel blockers (amlodipine), angiotensin converting enzyme (ACE) inhibitors (enalapril), beta-adrenergic receptor blockers (metoprolol), thiazide diuretics (bendrofluazide) and angiotensin II antagonists (various types and at various dosages, alone or in combination with thiazides, calcium channel blockers, beta-blockers and / or alpha-blockers). Tadalafil (10 mg, except for studies with angiotensin II antagonists and amlodipine using a dose of 20 mg) did not have a 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, changes in outpatient controlled blood pressure appeared to be related to the degree of blood pressure control. In this regard, in this study, in subjects with well-controlled blood pressure, the reduction in blood pressure was minimal and similar to that observed in healthy subjects. In this study, in subjects with uncontrolled blood pressure, the reduction was larger, although in most subjects this reduction was not associated with hypotensive symptoms. In patients receiving concomitant antihypertensive medicinal products, tadalafil 20 mg may induce a reduction in blood pressure, which (except for alpha blockers - see above) is generally minor and probably not clinically relevant. Evaluation of phase 3 clinical trial data showed no difference in adverse events in patients who took tadalafil with or without antihypertensive medicinal products. However, adequate clinical information should be provided to patients being treated with antihypertensive medicinal products regarding a possible decrease in blood pressure.
5-alpha reductase inhibitors
In a clinical study comparing tadalafil 5 mg co-administered with finasteride 5 mg and placebo plus finasteride 5 mg in the treatment of symptoms of benign prostatic hyperplasia, no new adverse reactions were identified. However, as a formal study was not performed. of drug interactions evaluating the effects of tadalafil and 5-alpha reductase inhibitors (5-ARIs) tadalafil should be used with caution when co-administered with 5-alpha reductase inhibitors.
CYP1A2 substrates (e.g. theophylline)
In a clinical pharmacology study, when 10 mg of tadalafil was co-administered with theophylline (a non-selective phosphodiesterase inhibitor), no pharmacokinetic interaction occurred. The only pharmacodynamic effect was a small increase (3.5 bpm) in heart rate. Although this effect is minor and of no clinical relevance in this study, it should be considered when these medicinal products are co-administered.
Ethinylestradiol and terbutaline
Tadalafil has been shown to cause an increase in the oral bioavailability of ethinylestradiol; a similar increase can be expected with oral administration of terbutaline, although the clinical consequence of this is uncertain.
Alcohol
Alcohol concentrations (mean maximum blood concentration of 0.08%) were not affected by co-administration of tadalafil (10 mg or 20 mg). Furthermore, no change in tadalafil concentrations was observed 3 hours after co-administration with alcohol. Alcohol was administered in such a way as to maximize the percentage of alcohol absorption (fasting overnight and without food for up to two hours after alcohol administration). Tadalafil (20 mg) did not increase the mean alcohol-induced decrease in blood pressure (0.7 g / kg or approximately 180 ml of 40% alcohol [vodka] in an 80 kg man), 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 a frequency similar to that seen with alcohol alone. The effect of alcohol on cognitive function was not augmented by tadalafil (10 mg).
Medicinal products metabolised by cytochrome P450
Tadalafil is not expected to cause "clinically significant inhibition or" induction of clearance of medicinal products metabolised by CYP450 isoenzymes. Studies have confirmed that tadalafil does not inhibit or induce CYP450 isoenzymes, 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 it affect warfarin-induced changes in prothrombin time.
Aspirin
Tadalafil (10 mg and 20 mg) did not potentiate the increase in bleeding time due to acetylsalicic acid.
Antidiabetic medicines
Specific interaction studies with antidiabetic medicinal products have not been performed.
04.6 Pregnancy and lactation
The use of CIALIS in women is not indicated.
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 / fetal development, parturition or postnatal development (see section 5.3). precautionary, it is preferable to avoid the use of CIALIS during pregnancy.
Feeding time
Available pharmacodynamic / toxicological data in animals have shown excretion of tadalafil in milk. A risk to nursing infants cannot be excluded. CIALIS should not be used during lactation.
Fertility
Effects that could indicate impaired fertility were observed in dogs. Two subsequent clinical studies suggest that this effect is unlikely in men, although decreased sperm concentration was observed in some men (see sections 5.1 and 5.3).
04.7 Effects on ability to drive and use machines
CIALIS has negligible influence on the ability to drive and use machines. Before driving and operating machines, patients should be aware of how they react to CIALIS, although the frequency of dizziness episodes was similar for placebo and tadalafil in clinical trials.
04.8 Undesirable effects
Summary of the safety profile
The most commonly reported adverse reactions in patients taking CIALIS for the treatment of erectile dysfunction or benign prostatic hyperplasia were headache, dyspepsia, back pain and myalgia, with an incidence increasing with increasing dose of CIALIS. Adverse reactions reported were transient, and generally mild or moderate. The largest number of headache cases reported with CIALIS administered once daily occurred within the first 10 to 30 days of initiation of treatment.
Table of adverse reactions
The table below lists the adverse reactions observed in spontaneous reporting and placebo-controlled clinical trials (comprising a total of 7116 patients treated with CIALIS and 3718 patients treated with placebo) for the on-demand and daily treatment of erectile dysfunction and for the treatment of benign prostatic hyperplasia with daily administration.
Frequency convention: very common (≥1 / 10), common (≥1 / 100,
1 Most patients had pre-existing cardiovascular risk factors (see section 4.4).
2 Post-marketing surveillance reported adverse reactions not observed in placebo-controlled clinical trials.
3 Most 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 changes, mainly sinus bradycardia, was reported in patients treated with tadalafil once daily compared to patients treated with placebo. Most of these ECG changes were not associated with adverse reactions.
Other special populations
There are limited data in patients over 65 years of age who have received tadalafil in clinical trials, for the treatment of erectile dysfunction or for the treatment of benign prostatic hyperplasia. In clinical trials with tadalafil 5 mg, taken once daily for the treatment of benign prostatic hyperplasia, dizziness and diarrhea have been reported more frequently in patients over 75 years of age.
04.9 Overdose
Single doses up to 500 mg have been administered to healthy subjects and multiple daily doses up to 100 mg have been administered to patients. Adverse events were similar to those seen at lower doses.
In the event of an overdose, necessary standard supportive measures should be employed.
Hemodialysis contributes negligibly to the elimination of tadalafil.
05.0 PHARMACOLOGICAL PROPERTIES
05.1 Pharmacodynamic properties
Pharmacotherapeutic group: urologicals, drugs used for erectile dysfunction.
ATC code: G04BE08.
Mechanism of action
Tadalafil is a selective and reversible inhibitor of cyclic guanosine monophosphate (cGMP) -specific phosphodiesterase type 5 (PDE5). When sexual stimulation results in the local release of nitric oxide, the inhibition of PDE5 by tadalafil causes an increase in the levels of cGMP in the corpus cavernosum. This results in relaxation of the smooth muscle and the flow of blood into the tissue of the penis. thus producing an erection. Tadalafil has no effect in the absence of sexual stimulation.
Pharmacodynamic effects
Education in vitro have shown that tadalafil is a selective inhibitor of PDE5. PDE5 is an enzyme found in smooth muscle of the corpus cavernosum, visceral and vascular smooth muscle, skeletal muscle, platelets, kidney, lung and cerebellum.
The effect of tadalafil is more potent on PDE5 than on other phosphodiesterases. Tadalafil is more than 10,000 times more potent for PDE5 than for PDE1, PDE2 and PDE4, enzymes that are present in the heart, brain, blood vessels, in the liver and other organs. Tadalafil is more than 10,000 times 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. In addition, tadalafil is about 700 times more potent for PDE5 than for PDE6, an enzyme in the retina responsible for phototransduction. In addition, tadalafil is more than 10,000 times more potent for PDE5 than for the PDE7 through the PDE10.
Clinical efficacy and safety
Three clinical studies were conducted in 1,054 patients in home treatment to define the period of response to CIALIS taken on demand. Tadalafil demonstrated statistically significant improvement in erectile function and the ability to have successful intercourse up to 36 hours after dosing as well as improved patients' ability to achieve and maintain erections compared to placebo. for successful intercourse as early as 16 minutes after dose administration.
Tadalafil given to healthy subjects compared to placebo did not cause significant differences in supine systolic and diastolic blood pressure (mean maximum reduction of 1.6 / 0.8 mm Hg, respectively), systolic and diastolic blood pressure when standing ( maximum mean reduction of 0.2 / 4.6 mm Hg, respectively) and no significant change in heart rate.
In a study to evaluate the effects of tadalafil on visual function with the aid of the Farnsworth-Munsell 100 hue test, no changes in color perception (blue / green) were detected. This finding is in line with the low affinity of tadalafil. for PDE6 compared to PDE5.
Across all clinical trials, reports of changes in color vision were rare (
Three clinical studies in men were performed to evaluate the potential effect on spermatogenesis of CIALIS, administered at doses of 10 mg per day (one 6-month study) and 20 mg per day (one 6-month study and one 9-month study ). In two of these studies, decreases in sperm counts and concentrations of unlikely clinical significance were observed in relation to treatment with tadalafil.
These effects were not associated with changes in other parameters such as motility, sperm morphology and the FSH hormone.
Tadalafil at doses of 2.5, 5 and 10 mg, taken once daily, was initially evaluated in 3 clinical studies involving 853 patients of various ages (21-82 years) and ethnicity, with erectile dysfunction of different severity (mild, moderate, severe) and etiology. In the two primary efficacy studies in the general population, the mean per-subject percentage of successful intercourse attempts was 57% and 67% with CIALIS 5 mg, 50% with CIALIS 2.5 mg versus 31% and 37% with placebo. In the study in patients with erectile dysfunction secondary to diabetes, the mean per-subject percentage of successful attempts was 41% and 46% with CIALIS 5 mg and 2.5 mg, respectively, compared with 28% with placebo. . Most patients in these three clinical trials responded to prior on-demand treatment with PDE5 inhibitors. In a subsequent study, 217 patients who were first treated with PDE5 inhibitors were randomized to CIALIS 5 mg once daily vs. placebo. The mean per-subject percentage of successful intercourse attempts was 68% for patients treated with CIALIS compared to 52% for patients treated with placebo.
In a 12-week study of 186 patients (142 treated with tadalafil, 44 with placebo) with erectile dysfunction secondary to a spinal cord injury, tadalafil significantly improved erectile function leading to a percentage of successful sexual intercourse. positive per subject, on average, 48% in patients treated with tadalafil 10 or 20 mg (flexible dosing, as needed) compared with 17% seen in patients treated with placebo.
Pediatric population
The European Medicines Agency has waived the obligation to submit the results of studies in all subsets of the pediatric population in the treatment of erectile dysfunction. See section 4.2 for information on pediatric use.
05.2 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 administration.
The absolute bioavailability of tadalafil following oral administration has not been determined.
The rate and duration of absorption of tadalafil are not affected by food, therefore CIALIS can be taken regardless of meals. The time of administration (morning versus evening) has no clinically relevant effect on the rate and duration of absorption. .
Distribution
The mean volume of distribution is approximately 63 L, indicating that tadalafil distributes to tissues.At therapeutic concentrations, 94% of tadalafil is bound to plasma 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 mainly metabolised by the cytochrome P450 (CYP) isoenzyme 3A4. The major circulating metabolite is methylcatecholglucuronide. This metabolite is at least 13,000 times less potent than tadalafil for PDE5. Consequently, it is not expected to be clinically active at observed metabolite concentrations.
Elimination
The mean clearance of tadalafil after oral administration is 2.5 l / hour and the mean half-life is 17.5 hours in healthy subjects.
Tadalafil is eliminated predominantly as an inactive metabolite, mainly in the faeces (approximately 61% of the dose) and to a lesser extent in the urine (approximately 36% of the dose).
Linearity / non-linearity
The pharmacokinetic profiles of tadalafil in healthy subjects are linear with respect to time and dose. At doses above 2.5-20 mg, tadalafil exposure (AUC) increases in proportion to dose. Steady-state plasma concentrations are achieved within 5 days of daily dosing.
The pharmacokinetic profiles determined in a population study in patients with erectile dysfunction are similar to those found in subjects without erectile dysfunction.
Special populations
Senior citizens
Healthy elderly subjects (65 years or older), after oral administration, had a lower clearance of tadalafil, resulting in a 25% higher exposure (AUC) than that observed in healthy subjects aged 19 to 45 years. This age-related effect is not clinically significant and does not require dosage adjustment.
Kidney failure
In clinical pharmacology studies, using a single dose of tadalafil (5 to 20 mg), tadalafil exposure (AUC) was approximately doubled in subjects with mild renal impairment (creatinine clearance 51 to 80 ml / min) or moderate (creatinine clearance 31 to 50 ml / min) and in subjects with end stage renal disease undergoing dialysis. In hemodialysis patients, Cmax was 41% higher than that observed in healthy patients. Hemodialysis contributes negligibly to the elimination of tadalafil.
Hepatic insufficiency
The exposure (AUC) to tadalafil in subjects with mild and moderate hepatic impairment (Child-Pugh Classes A and B) is comparable to the exposure in healthy subjects when administered at a dose of 10 mg. There is limited clinical data on the safety of CIALIS in patients with severe hepatic impairment (Child-Pugh class C). There are no data available on the administration of once daily doses of tadalfil to patients with hepatic insufficiency. If CIALIS is prescribed once daily, a careful case-by-case assessment of the benefit-risk ratio should be made by the prescribing physician.
Diabetic patients
Tadalafil exposure (AUC) in diabetic patients was approximately 19% lower than the AUC value in healthy subjects. This difference in exposure does not require dosage adjustment.
05.3 Preclinical safety data
Non-clinical data show no particular hazard for humans based on conventional studies of safety, pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential and toxicity for reproduction.
There was no evidence of teratogenicity, embryotoxicity or foetotoxicity in rats or mice that received up to 1,000 mg / kg / day of tadalafil. In a prenatal and postnatal development study in rats, no effect was observed with a dose of 30 mg / kg / day. In pregnant female rats, the calculated AUC for free drug at this dosage was approximately 18 times the AUC in humans at a dosage of 20 mg.
There was no impairment of fertility in male and female rats. In dogs treated for 6 to 12 months with tadalafil at daily doses of 25 mg / kg / day or more (resulting in at least 3-fold higher exposure [range 3 , 7-18.6] than that observed in humans with a single dose of 20 mg), there was a regression of the epithelium of the seminiferous tubule which in some dogs resulted in a reduction in spermatogenesis. See also section 5.1.
06.0 PHARMACEUTICAL INFORMATION
06.1 Excipients
Tablet:
lactose monohydrate,
croscarmellose sodium,
hydroxypropylcellulose,
microcrystalline cellulose,
sodium lauryl sulfate,
magnesium stearate.
Film coating:
lactose monohydrate,
hypromellose,
triacetin,
titanium dioxide (E171),
yellow iron oxide (E172),
red iron oxide (E172),
talc.
06.2 Incompatibility
Not relevant.
06.3 Period of validity
3 years.
06.4 Special precautions for storage
Store in the original package to protect from moisture. Do not store above 30 ° C.
06.5 Nature of the immediate packaging and contents of the package
Aluminum / PVC / PE / PCTFE blisters in cartons of 28 film-coated tablets.
06.6 Instructions for use and handling
No special instructions.
07.0 MARKETING AUTHORIZATION HOLDER
Eli Lilly Nederland B.V.
Grootslag 1-5, NL-3991 RA, Houten
Netherlands
08.0 MARKETING AUTHORIZATION NUMBER
EU / 1/02/237/006
035672068
09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION
Date of first authorization: 12 November 2002
Date of last renewal: 12 November 2012
10.0 DATE OF REVISION OF THE TEXT
D.CCE March 2014
