Brand name:
Eresta
INTERNATIONAL NONPROPRIETARY NAME:
Tadalafil
DRUG FORM: film coated tablets
DESCRIPTION: yellow drop-shaped film coated tablets.
COMPOSITION:
1 tablet contains:
Active substance: Tadalafil – 5 mg, 10 mg, 20 mg;
Excipients: lactose monohydrate, croscarmellose sodium, sodium lauryl sulfate, hydroxypropylcellulose (E463), microcrystalline cellulose, magnesium stearate (E572), film coating;
Film coating (for 5 mg and 10 mg tablets): Opadry II yellow 31F38002 (lactose monohydrate, hypromellose (HPMC) 15 Cp 2910, titanium dioxide (E171), iron oxide yellow (E172), macrogol type 4000/PEG).
Film coating (for 20 mg tablet): Opadray II yellow 31K32498 (lactose monohydrate, hypromellose (HPMC) 15 Cp 2910, titanium dioxide (E171), iron oxide yellow (E172), triacetin (E1518), iron oxide black (E172)).
Pharmacotherapeutic group
Drug products for the treatment of urinary diseases. Drug products for the treatment of erectile dysfunction.
ATC code: G04BE08
Pharmacological properties
Pharmacodynamics
Tadalafil is an effective, reversible, selective inhibitor of the specific type 5 (PDE5) phosphodiesterase of cyclic guanosine monophosphate (cGMP). When sexual ecitation causes local release of nitric oxide, PDE5 inhibition by Tadalafil leads to increased levels of cGMP in the cavernous body of penis. The consequence of this is arterial smooth muscles relaxation and blood flow to the penile tissues that causes erection. Tadalafil has no effect without sexual ecitation.
The effect of PDE5 inhibition on cGMP concentration in the cavernous body is also observed in the smooth muscles of the prostate, bladder and their blood vessels. The resulting vascular relaxation increases blood perfusion, which can be the mechanism for reducing the severity of symptoms of benign prostatic hyperplasia (BPH). These vascular effects may be complemented by inhibition of bladder afferent nerve activity and relaxation of prostate and bladder smooth muscle.
In vitro studies have shown that Tadalafil is a selective inhibitor of PDE5 found in smooth muscles of the cavernous body, in smooth muscles of the vessels in internal organs, in skeletal muscles, platelets, kidneys, lungs and cerebellum. Tadalafil effect on PDE5 is more intense than that on other phosphodiesterases. Tadalafil is 10000 times more potent against PDE5 than against PDE1, PDE2 and PDE4, localized in the heart, brain, blood vessels, liver, leukocytes, skeletal muscles and other organs. Tadalafil is 10000 times more effective in blocking PDE5 than PDE3, the enzyme found in the heart and blood vessels. This selectivity for PDE5 over PDE3 is important because PDE3 is the enzyme involved in heart muscle contraction. In addition, Tadalafil is about 700 times more effective against PDE5 than PDE6, found in the retina and responsible for photo-transmission. Tadalafil is also 10 000 times more potent against PDE5 compared to that on PDE7, PDE8, PDE9 and PDE10.
The results of three clinical studies with 1504 patients in determination of the Tadalafil effect time period demonstrated statistically significant improvement in erectile function, as well as its efficacy within 36 hours and the effect observed in 16 minutes after the dose intake compared to placebo. Tadalafil administered to healthy volunteers showed no significant difference when compared to placebo in terms of systolic and diastolic blood pressure in the supine position (mean maximum reduction of 1.6/0.8 mmHg, respectively), systolic and diastolic blood pressure in the standing position (mean maximum reduction of 0.2/4.6 mmHg, respectively) and no significant change in heart rate.
In a study of Tadalafil effect on vision using the Farnsworth-Munsell 100-hue color perception assessment test it was found that Tadalafil did not worsen color recognition (blue/green). The data obtained in the clinical study proved the low affinity of Tadalafil to PDE6 compared to PDE5. Changes in color recognition were rarely (< 0.1%) reported in clinical studies.
Three clinical studies involved men patients were conducted to evaluate the drug product potential effects on spermatogenesis when administered at a dose of 10 mg (one 6-month study) and 20 mg (6-month study and 9-month study) taken once a day. Two out of the three studies observed clinically insignificant decrease in sperm count and concentration related to Tadalafil administration. These effects were not associated with changes in other characteristics such as sperm motility, morphology, and blood level of follicle-stimulating hormone. Tadalafil in doses from 2 mg to 100 mg was evaluated in 16 clinical studies involved 3 250 patients including patients with erectile dysfunction of different severity (moderate, moderately severe, significant), different etiologies, patients of different age (21 to 86 years old), and different ethnic groups.
Most patients had erectile dysfunction for at least one year. In primary efficacy studies, the improvement rate was 81% in the drug group compared to 35% in the placebo group. In addition, improvement was reported in patients with erectile dysfunction of various degrees of severity (success rates were 86%, 83% and 72% in patients with moderate, moderate severe and significant erectile dysfunction, respectively, compared to 45%, 42% and 19% in the placebo group).
Pharmacokinetics
Absorption
Tadalafil is rapidly absorbed after oral administration. The average maximum plasma concentration (Cmax) is reached on average in 2 hours after oral administration. Absolute bioavailability of Tadalafil after oral administration has not been established. The rate and extent of Tadalafil absorption do not depend on food intake therefore the drug can be taken regardless of food intake. The time of administration (morning or evening) had no clinically significant effect on absorption rate and extent.
Distribution
Average volume of distribution is about 63 liters, indicating that Tadalafil is distributed in the body tissues. At therapeutic concentration 94% of Tadalafil in plasma is bound to proteins. Protein binding is not altered in case of impaired renal function.
In healthy volunteers, less than 0.0005% of the administered dose is found in seminal fluid.
Metabolism
Tadalafil is mainly metabolized with the use of cytochrome P450 isoenzyme CYP3A4. The main circulating metabolite is methyl catechol glucuronide. This metabolite is at least 13000 times less active against PDE5 than Tadalafil. Thus, the metabolite is not expected to be clinically active at detectable concentrations.
Excretion
In healthy volunteers, the mean clearance of Tadalafil taken orally is 2.5 l/hour and the mean elimination half-life is 17.5 hours. Tadalafil is excreted predominantly as inactive metabolites, mainly with the feces (about 61% of the dose) and, to a lesser extent, with the urine (about 36% of the dose).
Linearity/Nonlinearity
Tadalafil pharmacokinetics in healthy volunteers is linear with respect to time and dose. In the dose range from 2.5 to 20 mg, the area under the concentration-time curve (AUC) increases proportionally to the dose. Equilibrium plasma concentrations are achieved within 5 days when taking the drug once a day every day.
Tadalafil pharmacokinetics in patients with erectile dysfunction is similar to that in patients without erectile dysfunction.
Special Patient groups
Elderly patients
Healthy elderly volunteers (65 years old and above) had lower clearance of Tadalafil taken orally reflected in a 25% increase in the area under the concentration-time curve compared to healthy volunteers aged 19 to 45 years old. This difference is not clinically significant and does not require dose adjustment.
Patients with renal impairment
In clinical pharmacology studies with a single dose of Tadalafil (5-20 mg), Tadalafil AUC exposure was almost doubled in patients with mild (creatinine clearance 51 to 80 mL/min) or moderate (creatinine clearance 31 to 50 mL/min) renal impairment, also in dialysis patients with end-stage renal failure. In hemodialysis patients the maximum plasma concentration (Cmax) was 41% higher than that in healthy volunteers. The effect of hemodialysis on Tadalafil excretion can be neglected.
Patients with hepatic impairment
Tadalafil exposure in patients with mild to moderate hepatic impairment (Child-Pugh classes A and B) is comparable to that in healthy volunteers when taken at a dose of 10 mg. Clinical safety data on Tadalafil administration in patients with severe hepatic impairment (Child-Pugh class C) are limited. If Tadalafil is prescribed, then the physician should carefully evaluate the benefit-risk ratio. There is no data regarding the use of the drug product at a dose higher than 10 mg in patients with hepatic impairment.
Patients with Diabetes Mellitus
In patients with diabetes mellitus, the exposure (AUC) of Tadalafil was lower by about 19% than in healthy volunteers. This difference does not require dose adjustment.
Indications for use
Treatment of erectile dysfunction in adult men. The drug product is effective in case of sexual excitation.
5 mg dose: treatment of signs and symptoms of benign prostatic hyperplasia in adult men.
Eresta 10 mg and 20 mg is not recommended for daily administration (see “Dosage and Administration”).
It is not indicated for use in women.
Dosage and Administration
For internal use
Treatment of erectile dysfunction in adult men
The recommended dose of Eresta is 10 mg with or without food, before sexual activity. Patients who had no sufficient effect of Tadalafil when prescribed 10 mg of Eresta, may be prescribed 20 mg of the drug product. It should be taken at least 30 minutes before sexual activity. The maximum recommended frequency of administration is once a day. Eresta, 10 mg and 20 mg tablets are not recommended for continuous daily use.
In patients planning frequent use of Tadalafil (at least twice a week), a low daily dose of Tadalafil may be appropriate based on patient choice and doctor recommendation.
Treatment of signs and symptoms of benign prostatic hyperplasia in adult men (BPH)
The recommended dose is 5 mg once daily at approximately the same time, with or without food. The recommended daily dose for adult males with BPH and erectile dysfunction is also 5 mg once a day at approximately the same time. Patients who poorly tolerate the treatment with Tadalafil 5 mg should consider alternative therapy, as the efficacy of Tadalafil 2.5 mg has not been proved.
Special Patient Groups
Elderly men: no dose adjustment is required.
Men with renal insufficiency: dose adjustment in patients with mild to moderate renal insufficiency is not required. For patients with severe renal impairment the maximum recommended dose is 10 mg, daily intake regimen is not recommended.
Daily intake of Tadalafil at the dose of 2.5 g or 5 mg for the treatment of BPH or erectile dysfunction is not recommended in patients with severe renal impairment.
Patients – men with hepatic impairment: the recommended dose is 10 mg before sexual activity and does not depend on food intake. Taking into account limited safety data on the drug administration in patients with severe liver failure (Child-Pugh class C), the doctor should carefully evaluate the benefit-risk ratio of Tadalafil when prescribed in this group of patients. There are no data on Tadalafil administration at a dose higher than 10 mg in patients with severe hepatic impairment.
Daily intake of Tadalafil at the dose of 2.5 g or 5 mg for treatment of BPH or erectile dysfunction has not been studied in patients with liver failure therefore the doctor should carefully evaluate the benefit-risk ratio of the drug product.
Patients – men with Diabetes Mellitus: no dose correction required
Children
Tadalafil is not indicated for use in children. The drug product efficacy and safety in patients below 18 years old have not been established.
Side effect
The most frequently reported adverse reactions in patients taking Tadalafil are headache, dyspepsia, back pain, myalgia; the incidence is increasing with the drug dose increased. The adverse reactions reported were usually transient and mostly of minor or moderate severity. Most cases of headache have been noted with Tadalafil taken once a day during the first 10-30 days from the beginning of the treatment.
Adverse reactions are classified by classes of organ systems and frequency: very frequent (≥1/10); frequent (≥1/100, < 1/10); infrequent (≥1/1000, < 1/100); rare (≥1/10000, <1/1000); very rare (<1/10000).
Immune system disorders: infrequent: hypersensitivity reactions; rare: angioedema2.
Nervous system: often: headache; infrequently: dizziness; rarely: stroke1 (including hemorrhagic phenomena), fainting, transient ischemic attacks1, migraine2, seizures, transient amnesia.
Eye disorders: infrequently: blurred vision, ophthalmalgia; rarely: visual field defects, eyelid edema, conjunctival hyperemia, non-arterial anterior ischemic optic neuropathy (NAION)2, retinal vein occlusion2.
Ear and labyrinth disorders: infrequently: tinnitus; rare: sudden hearing loss.
Cardiac disorders1: infrequently: tachycardia, palpitations; rare: myocardial infarction, unstable angina2, ventricular arrhythmia2.
Vascular disorders: often: flushes; infrequently: hypotension3, hypertension.
Respiratory, thoracic and mediastinal disorders: often: nasal congestion; infrequently: dyspnea, nose bleeding.
Gastrointestinal disorders: often: dyspepsia, gastroesophageal reflux; infrequently: abdominal pain.
Skin and subcutaneous tissue disorders: infrequently: rash, hyperhidrosis (increased sweating); rarely: urticaria, Stevens-Johnson syndrome2, exfoliative dermatitis2.
Musculoskeletal and connective tissue disorders: frequently: back pain, myalgia and pain in extremities.
Renal and urinary disorders: infrequently: hematuria
Reproductive system and breast disorders: infrequently: prolonged erection; rare: priapism, bleeding from penis, hemospermia.
General and injection site reactions: infrequently: chest pain1; rarely: facial edema2, sudden coronary death1,2.
1 - majority of patients experienced these adverse reactions had cardiovascular risk factors;
2 - adverse reactions identified in postmarketing studies were not observed during placebo-controlled clinical studies;
3 - more frequently reported when Tadalafil was co-administered with antihypertensive agents.
Description of specific adverse reactions
A slightly higher prevalence of ECG abnormalities, primarily sinus bradycardia, was reported in patients received Tadalafil once a day compared with patients received placebo. Most of these ECG abnormalities were not associated with adverse reactions.
Specific Patient Groups
Data on Tadalafil administration in patients above 65 years old obtained in clinical studies for the treatment of erectile dysfunction are limited. In clinical studies when Tadalafil is taken at the dose of 5 mg once a day for the treatment of prostatic hyperplasia, dizziness and diarrhea were more frequently reported cases observed in patients above 75 years old.
Contraindications
- Established hypersensitivity to Tadalafil or any substance contained in the drug product.
- In clinical studies Tadalafil has shown the enhanced hypotensive effect of nitrates. This is expected to be a consequence of combined effects of nitrates and Tadalafil on the nitric oxide/ cGMP pathway. Thus, Tadalafil is contraindicated in patients taken organic nitrates in any dosage form.
Tadalafil should not be used in men with heart diseases to whom sexual activity is not recommended. The potential risk of complications from sexual activity in patients with cardiovascular disease should be considered.
Groups of patients with cardiovascular disease that have not been included in clinical studies; therefore Tadalafil is contraindicated for administration in these groups:
- Patients with myocardial infarction observed within the past 90 days;
- Patients with unstable angina pectoris or angina pectoris occurring during sexual activity;
- Cardiac patients Class 2 or higher (according to New York Heart Association) within the last 6 months;
- Patients with uncontrolled cardiac rhythm disturbances, arterial hypotension (< 90/50 mm Hg), or uncontrolled arterial hypertension;
- Patients suffered from stroke within the last 6 months.
Tadalafil is contraindicated in patients who lost vision in one eye due to nonarteritic anterior ischemic optic neuropathy (NAION), regardless of whether this is related to previous use of PDE5 inhibitors.
Concomitant use of PDE5 inhibitors, including Tadalafil, with guanylate cyclase stimulators, such as riociguat, is contraindicated because it can potentially lead to symptomatic hypotension.
Precautions
Before administration of the drug product Eresta
Before administration of this drug product, tests and examinations should be performed to diagnose erectile dysfunction and identify the potential causes. Before starting any treatment for erectile dysfunction, the cardiovascular status of patients should be considered, as there is certain cardiac risk associated with sexual activity. Tadalafil causes vasodilation, which may result in a slight transient decrease in blood pressure and thus potentiate the hypotensive effect of nitrates.
Evaluation of erectile dysfunction should include determination of its potential causes and identification of appropriate course of treatment after proper physical examination. It is not known whether Tadalafil is effective in patients who have undergone pelvic bone surgery or radical prostatectomy without nerve preservation.
Cardiovascular system
Serious cardiovascular disorders, including myocardial infarction, sudden cardiac death, unstable angina, ventricular arrhythmias, stroke, transient ischemic attack, chest pain, palpitations and tachycardia have been reported in some studies. Most patients reported about such cases had a history of risk factors. At the same time, it cannot be determined whether these disorders are directly related to risk factors, to Tadalafil intake, or to the combination of these or any other factors.
Tadalafil may cause decrease in blood pressure in patients receiving concomitant therapy with antihypertensive agents. Before starting daily administration of Tadalafil, possible dose adjustment of antihypertensive agents should be considered.
Caution should be exercised when prescribing this drug product to patients taking α1-adrenoblockers, e.g. Doxazosin, as concomitant use may lead to symptomatic hypotension in some patients. Combined use of Tadalafil and Doxazosin is not recommended.
Eye disorders
There have been reported cases of NAION and visual disorders associated with Tadalafil and other PDE5 inhibitors administration. In case of sudden loss of vision patients should be advised to discontinue Tadalafil and seek medical attention immediately.
Liver and kidney dysfunction
Due to the increased Tadalafil exposure (AUC), limited clinical data and ineffectiveness of hemodialysis, daily intake is not recommended in patients with severe renal dysfunction.
Clinical data on safety of Tadalafil taken in a single dose in patients with severe hepatic dysfunction (Child-Pugh class C) are limited. When prescribing the drug to such patients, the doctor should carefully evaluate the individual benefit/risk of the therapy.
Sudden reduction or loss of hearing
Cases of sudden hearing loss have been reported after Tadalafil administration. Although other risk factors (such as age, diabetes, arterial hypertension and history of hearing loss) presented in some cases, patients should be advised to discontinue Tadalafil and ask for immediate medical attention in case of sudden reduction or loss of hearing.
Priapism and anatomical deformity of penis
Patients should be advise to seek immediate medical attention in case of erection lasting for 4 hours or longer. Untimely treatment of priapism leads to penile tissue damage, which may result in long-term loss of potency.
Tadalafil should be used with caution in patients with anatomical deformities of penis (angular curvature, cavernous fibrosis or Peyronie disease) or in patients with predisposition to priapism (sickle cell anemia, multiple myeloma or leukemia).
Co-administration with CYP3A4 inhibitors
It is necessary to prescribe Tadalafil with caution to patients treated with strong CYP3A4 inhibitors (ritonavir, saquinavir, ketoconazole, itraconazole, erythromycin), as when coadministered with Tadalafil, an increase in Tadalafil exposure (AUC) is observed.
Co-administration with other medicinal products to treat erectile dysfunction
Safety and efficacy Tadalafil co-administered with other medicinal products for treatment of erectile dysfunction have not been studied. Patients should not be advised to take Eresta in such combinations.
Excipients
Eresta contains lactose. The drug product should not be administered to patients with rare hereditary diseases of lactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption syndrome.
Effect on ability to drive and operate machinery
Tadalafil effect on ability to drive and operate machinery and mechanisms is insignificant. Although frequency of dizziness reported in clinical studies with placebo and Tadalafil was similar, patients should be awared of how the drug affects them before driving or operating machinery.
Use in pregnancy and lactation period
Eresta is not indicated for women
Fertility
In two clinical studies it was suggested that impaired fertility was not expected in human, although decreased sperm concentration was observed in some men.
Overdose
When Tadalafil was administered to healthy volunteers in a single dose of up to 500 mg and when used repeatedly up to 100 mg/day by patients with erectile dysfunction, the undesirable effects were the same as with lower doses. In case of overdose, standard symptomatic treatment should be recommended. Tadalafil excretion is practically not affected by hemodialysis.
Drug-to-drug interactions
Drug interactions with Tadalafil
Cytochrome CYP450 inhibitors
Tadalafil is mainly metabolized using CYP3A4 enzyme. Selective inhibitor of CYP3A4, Ketoconazole (200 mg daily) increases Tadalafil (10 mg) exposure (AUC) twice and Cmax by 15% compared to Tadalafil (AUC) and Cmax when used alone. The selective CYP3A4 inhibitor, Ketoconazole (400 mg daily) increases Tadalafil (20 mg) exposure (AUC) 4 times and Cmax by 22%. Ritonavir, the protease inhibitor, (200 mg twice a day), which is also the inhibitor of CYP3A4, 2C9, 2C19 and 2D6, increases Tadalafil exposure (AUC) twice but does not change Cmax. Although specific interactions have not been studied, it can be suggested that when co-administered with other protease inhibitors such as saquinavir, or other CYP3A4 inhibitors such as erythromycin, clarithromycin, itraconazole and grapefruit juice they increase Tadalafil plasma concentration and should therefore be used with caution. As a consequence, the incidence of adverse reactions can be increased.
Transport proteins
The effect of transport proteins, such as p-glycoproteins, on Tadalafil distribution is unknown. Thus, there is a possibility of drug interactions mediated by inhibition of transport proteins.
Inducers of Cytochrome CYP450
Rifampin – the selective CYP3A4 inducer reduced Tadalafil exposure (AUC) by 88% compared to AUC of Tadalafil (10 mg) taken alone. It can be suggested that this decrease in concentration would result in decrease of Tadalafil efficacy. Concomitant use of other CYP3A4 inducers such as phenobarbital, phenytoin and carbamazepine may also reduce Tadalafil plasma concentration.
Tadalafil effect on other drug products
Nitrates
In clinical studies, Tadalafil (5 mg, 10 mg and 20 mg) demonstrated an ability to increase the hypotensive effects of nitrates. Thus, Tadalafil administration to patients treated with any form of organic nitrates is contraindicated. When the patient prescribed any dose of Tadalafil (2.5 to 20 mg), should use nitrates that are medically necessary in a life-threatening condition, at least 48 hours should have elapsed after the last dose of Tadalafil before nitrate medication is considered. In such a case, nitrates should only be administered under close medical supervision with appropriate hemodynamic monitoring.
Antihypertensive drugs (including calcium channel blockers)
Co-administration of Tadalafil (5 mg daily dose or 20 mg as a single dose) with the alpha-adrenoreceptor blocker doxazosin (4-8 mg daily dose) increases the blood-pressure lowering effect in a significant manner. This effect lasts at least 12 hours and may be manifested by individual symptoms, including dizziness. This combination of drugs is not recommended for use.
In interaction studies involving a limited number of healthy volunteers, the above effects were not reported when coadministered with Alfuzosin or Tamsulosin. Caution should be exercised when prescribing Tadalafil to patients treated with alpha-adrenoreceptor blockers, especially the elderly. Treatment should be started with the lowest dose and the dose should be gradually increased.
In clinical pharmacology studies the potential of Tadalafil to enhance the hypotensive effects of major antihypertensive drugs was investigated. Major classes of drug products investigated in this studies included: calcium channel blockers (amlodipine), ACE inhibitors (enalapril), β-adrenoreceptor blockers (metoprolol), thiazide diuretics (bendrofluazide), and angiotensin II receptor blockers (alone and in combination with thiazide diuretics, calcium channel blockers, β-adrenoreceptor blockers, and/or a-adrenoreceptor blockers). Tadalafil showed no significant interaction with the above-mentioned classes of drug products. In another clinical pharmacology study Tadalafil was studied in combination with multiple hypotensive medications (up to four classes). In patients who took multiple antihypertensive agents, changes in blood pressure were dependent on the level of blood pressure control. Thus, in patients with well-controlled blood pressure, the decrease in blood pressure was minimal and similar to that seen in healthy subjects. In patients whose blood pressure was not controlled, significant decrease in blood pressure was observed, although in majority of patients this decrease in blood pressure was not associated with hypotensive symptoms.
In patients receiving concomitant therapy with antihypertensive drug products, the use of Tadalafil 20 mg may lead to a decrease in blood pressure, which (except cases of concomitant use of alpha-adrenoreceptor blockers) is insignificant and clinically insignificant. Analysis of phase III clinical study results showed no difference in adverse reactions in patients treated with Tadalafil with or without antihypertensive. However, appropriate clinical advice should be given to patients on possible decrease in blood pressure when they are treated with antihypertensive drug products and Tadalafil, respectively.
Riociguant
During preclinical studies, an additive hypotensive effect was found in concomitant administration of PDE5 inhibitors with riociguat. During the studies it was found that riociguat enhances the hypotensive effect of PDE5 inhibitors. There was no evidence of favorable clinical effect of this combination in the study population. Concomitant use of riociguat with PDE5 inhibitors, including Tadalafil, is contraindicated.
Inhibitors of 5-alpha (α)-reductase
No new adverse reactions were observed in a clinical study that compared Tadalafil 5 mg coadministered with Finasteride 5 mg to placebo and Finasteride 5 mg aimed to reduce the severity of symptoms of BPH (benign prostatic hyperplasia). 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.
СYР1А2 substrates (e.g., Theophylline)
In a clinical pharmacology study no pharmacokinetic interaction was observed when Tadalafil was administered with Theophylline (a non-selective phosphodiesterase inhibitor). The only pharmacodynamic effect was a slight increase in heart rate. Although this effect is minor and was of no clinical significance in this study, it should be considered when co-administering these medicinal products.
Ethinylestradiol and Terbutaline
Tadalafil increased the bioavailability of Ethinylestradiol oral dosage forms. This increase in bioavailability may be expected when co-administered with Terbutaline, although the clinical consequence of this combination is uncertain.
Alcohol
Alcohol (mean maximum blood concentration 0.08%) had no effect on Tadalafil in combined use. There were also no changes in Tadalafil concentrations over the next three hours after concomitant administration of alcohol with Tadalafil. Alcohol was administered in a manner that maximized alcohol absorption (rapid ingestion without food within 2 hours after alcohol) Tadalafil did not cause statistically significant decrease in blood pressure produced by alcohol (0.7 g/kg), but postural dizziness and orthostatic hypotension were observed in some patients. 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.
Drug products metabolized by cytochrome P450
Tadalafil is not expected to cause clinically significant clearance inhibition or induction for drug products metabolized by CYP450 isoforms. In clinical studies it has been 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 had no clinically significant effect on exposure (AUC) to S-warfarin or R-warfarin (CYP2C9 substrates), nor did Tadalafil affect changes in prothrombin time induced by warfarin.
Aspirin
Tadalafil did not potentiate the increase in bleeding time caused by acetylsalicylic acid.
Antidiabetic drug products
Specific interaction studies of Tadalafil with antidiabetic drugs have not been conducted.
Storage conditions and expiry period
Store at temperature not above 25°С.
Keep out of reach of children!
Shelf life – 3 years. Do not use after expiration date on the package.
Prescription status
On prescription
Package
5 mg dose: 14 tablets in a blister made of PVC/PE/PVDC film and flexible aluminum foil. 1 or 2 blisters together with the patient information leaflet in a carton pack.
10 mg dose: 1 tablet in a blister made of PVC/PE/PVDC film and flexible aluminum foil. 1 or 2 blisters together with the patient information leaflet in a carton pack.
20 mg dose: 1 tablet in a blister made of PVC/PE/PVDC film and flexible aluminum foil. 1, 2 or 4 blisters together with the patient information leaflet in a carton pack.
Manufacturer Information
Foreign Production and Trade Unitary Enterprise “Reb-Pharma”, 223216, Republic of Belarus, Minsk region, Chervensky district, Smilovichi, Sadovaya St., 1, tel./fax: (+375) 17 240 26 35, e-mail: rebpharma@rebpharma.by, http://www.rebpharma.by
Comment type is not specified in the component properties.