The instruction for medical use of ARISTA medicine the Trade name of Arist Mezhdunarodnoye the unlicensed name Tadalafil Lekarstvennaya the Tablet form, film coated 20 mg Structure One tablet contains active agent – tadalafit 20 mg, excipients: lactoses monohydrate, croscarmellose sodium, sodium lauryl sulfate, hydroxypropyl cellulose, cellulose microcrystalline, magnesium stearate, structure of a cover: Опадри® II yellow 31K32498 (lactoses monohydrate, gipromelloz, titan dioxide (E171), ferrous oxide yellow, triacetin, ferrous oxide black). Description of the Tablet, teardrop shape, yellow color, film coated. Pharmacotherapeutic group Drugs for treatment of urological diseases. Other drugs for treatment of urological diseases, including spasmolysants. Drugs for treatment of disturbances of an erection. Tadalafil. The ATX G04BE08 code tadalafit the Pharmacological Pharmacokinetics Absorption Later properties of intake quickly is soaked up. The maximum concentration is reached on average in 2 hours. Speed and extent of absorption do not depend on meal. Time of administration of drug (morning or evening) has no clinically significant effect on the speed and extent of absorption. The pharmacokinetics of a tadalafil at healthy faces is linear concerning time and a dose. The pharmacokinetics of a tadalafil at patients with dysfunction of an erection is similar to drug pharmacokinetics at persons without dysfunction of an erection. Distribution the Average volume of distribution makes about 63 l. In therapeutic concentration of 94% of a tadalafil contacts proteins of blood plasma. At healthy faces & lt, 0.0005% of the entered dose reveal in sperm. Metabolism Is metabolized mainly with participation of an isoenzyme of CYP3A4. The main circulating metabolite is metilkatekholglyukuronid. It by 13,000 times is less active concerning FDE-5, than tadalafit. Therefore, this metabolite hardly is clinically significant. Removal At healthy faces average elimination half-life – 17.5 hours. Tadalafil is brought mainly in the form of inactive metabolites, generally with a stake (about 61% of a dose) and to a lesser extent – with urine (about 36% of a dose). Special groups of the population Elderly patients At healthy people of advanced age (65 years and more) lower clearance of a tadalafil is defined that is expressed in increase in AUC by 25% in comparison with healthy faces aged from 19 up to 45 years. This distinction is not clinically significant and does not demand selection of a dose. At patients with a renal failure, including the patients who are on a hemodialysis, AUC is more, than at healthy faces. Linking with proteins does not change in a renal failure. The pharmacokinetics of a tadalafil at patients with a slight or medium-weight liver failure is comparable with that at healthy faces. Concerning patients with a heavy liver failure (class C on a scale of Chayld-Pyyu) data are not available. At patients with diabetes against the background of use of a tadalafil AUC was about 19% less, than at healthy faces. This distinction does not demand change of a dose. A pharmacodynamics Drug for treatment of disturbances of an erection. Is reversible selection inhibitor of specific phosphodiesterase of type 5 (FDE-5) of the cyclic guanozinmonofosfat (tsGMF). When sexual excitement causes local release of nitrogen oxide, FDE-5 inhibition tadalafily leads to increase in the tsGMF level in a cavernous body of a penis. The relaxation of unstriated muscles of arteries and inflow of blood to penis tissues is a consequence of it, as causes an erection. Tadalafil does not render effect in the absence of sexual stimulation. The researches in vitro showed that tadalafit is selection FDE-5 inhibitor. FDE-5 – the enzyme found in unstriated muscles of a cavernous body, in unstriated muscles of vessels of internals, in skeletal muscles, thrombocytes, kidneys, lungs, a cerebellum. Action of a tadalafil on FDE-5 is more active, than on other phosphodiesterases. Tadalafil is 10,000 times more active concerning FDE-5, than concerning FDE-1, FDE-2, FDE-4, FDE-7 which are localized in heart, a brain, blood vessels, a liver, leukocytes, skeletal muscles and in other bodies. Tadalafil 10,000 times more active blocks FDE-5, than FDE-3 – enzyme which is found in heart and blood vessels. This selectivity concerning FDE-5 in comparison with FDE-3 is important as FDE-3 is the enzyme which is taking part in reduction of a cardiac muscle. Besides, tadalafit about 700 times more actively concerning FDE-5, than concerning the FDE-6 found in a retina and which is responsible for phototransfer. Tadalafil also shows action by 9,000 times more powerful concerning FDE-5, in comparison with its influence on FDE-8, FDE-9 and FDE-10, and by 14 times more powerful concerning FDE-5 in comparison with FDE-11. Tadalafil improves an erection and a possibility of carrying out successful sexual intercourse. Drug works within 36 hours. The effect is shown in 16 minutes after administration of drug in the presence of sexual excitement. Tadalafil does not cause reliable change of the systolic and diastolic arterial blood pressure (ABP) in healthy faces, in comparison with placebo, in a prone position (average maximum decrease in the ABP is 1.6/0.8 mm Hg. respectively) and standing (average maximum decrease in the ABP is 0.2/4.6 mm Hg. respectively). Tadalafil does not cause reliable change of heart rate. Tadalafil does not cause changes of recognition of color (blue/green) that is explained by its low affinity to FDE-6. Besides, influence of a tadalafil on visual acuity, the electroretinogram, intraocular pressure and size of a pupil is not noted. For the purpose of assessment of the impact of a tadalafil at daily reception on a spermatogenesis several researches were conducted. In one of researches the undesirable influence on morphology of spermatozoa and their mobility was not observed. In one of researches the decrease in average concentration of spermatozoa in comparison with placebo was revealed. Decrease in concentration of spermatozoa was connected with higher frequency of an ejaculation. Besides, tadalafit did not cause undesirable changes of content of testosterone, luteinizing hormone and follicle-stimulating hormone in blood plasma in comparison with placebo. Indications – treatment of erectile dysfunction. Drug is effective only in the presence of sexual stimulation. The route of administration and doses the Drug Arista is taken by adult (men) inside, irrespective of meal. The recommended dose makes 20 mg before expected sexual activity. The drug can be taken in 16 minutes before sexual activity. The efficiency of a tadalafil can remain on an extent till 36 o’clock after reception of a dose. The maximum recommended reception frequency – 1 time a day. Special groups of the population correction of a dose is not required from patients of advanced age (65 years and are more senior), patients with a slight and moderate renal failure, patients with diabetes. The maximum recommended Arista’s dose at patients with a liver failure and a heavy renal failure makes 10 mg. There are limited clinical data on safety of use of Arist for patients with a heavy liver failure (class C on classification of Chayld-Pyyu). In case of Arista’s appointment in this group, carrying out the careful analysis advantage/risk individually is necessary for each patient. There are no relevant data on purpose of a dose more than 10 mg to patients with a liver failure. Children and teenagers up to 18 years Arista is not applied to treatment of erectile dysfunction at children and teenagers up to 18 years. Side effects the Side reactions which were found more often than in isolated cases are listed according to the following gradation: very often (≥ 10%), it is frequent (≥ 1%, & lt, 10%), sometimes (≥ 0.1%, & lt, 1%), is rare (≥ 0.01%, & lt, 0.1%), is extremely rare (& lt, 0.01%), frequency is unknown (it is impossible to estimate the frequency of emergence of reactions on the available data). Often ¾ a headache ¾ congestion of a nose ¾ dyspepsia, a gastroesophageal reflux ¾ a dorsodynia, myalgia, extremity pain ¾ blood inflow/inflow ¾ dizziness ¾ diarrhea at patients of advanced age (65 years are also more senior) ¾ nausea ¾ fatigue Sometimes ¾ reactions of hypersensitivity ¾ dizziness ¾ illegibility of visual perception, pain in an eyeball ¾ a ring in ears ¾ tachycardia, a cardiopalmus, gipotenziya2, hypertensia ¾ short wind, nasal bleeding ¾ an abdominal pain ¾ rash, a hyperhidrosis (the increased perspiration) ¾ a hamaturia, bleeding from a penis, a hemospermia ¾ pain in grudi1 ¾ vomiting ¾ peripheral swell ¾ conjunctiva hyperaemia Seldom ¾ a Quincke’s disease ¾ a stroke (including ONMK on hemorrhagic type), the syncope, the tranzitorny ischemic attacks (TIA) 1, migren3, attacks/spasm, tranzitorny amnesia ¾ disturbance of fields of vision ¾ the lobby which is not connected with arteritis ischemic optical neuropatiya3, occlusion of vessels setchatki3 ¾ a sudden hearing loss ¾ a myocardial infarction, unstable stenokardiya3, ventricular aritmiya3 ¾ a small tortoiseshell, Stephens-Johnsona3 syndrome, exfoliative dermatit3 ¾ a long erection, priapizm3 ¾ swelled litsa3, sudden cordial smert1,3 1 Were observed at the patients who earlier have cardiovascular risk factors. However it is impossible to define precisely whether these phenomena directly are connected with these risk factors, Arista, sexual excitement, or with a combination of these or other factors. 2 it was In most cases noted at patients who already accepted antihypertensives. 3 Side reactions found during the post-market researches, which were not observed during clinical placebos – controlled researches. Contraindications ¾ hypersensitivity to a tadalafil or to any substance which is a part of drug ¾ administration of drugs containing any organic nitrates ¾ existence of contraindications to sexual activity at patients with diseases of a cardiovascular system: a myocardial infarction during the last 90 days, unstable stenocardia, emergence of an attack of stenocardia during sexual intercourse, the heart failure of the II-IV classes on classification of the New York cardiological association (NYHA) which developed within the last 6 months, uncontrollable arrhythmia, arterial hypotension (the ABP less than 90/50 mm Hg.), uncontrollable arterial hypertension, an ischemic stroke within the last 6 months ¾ loss of sight on one eye owing to the front ischemic optical neuropathy (NAPION) which is not connected with arteritis (regardless of communication with intake of FDE-5 inhibitors) ¾ a concomitant use of a docsazozin and also medicines for treatment of erectile dysfunction ¾ frequent (more than 2 times a week) use for patients with chronic kidney disease (KK less than 30 ml/min.) ¾ hereditary intolerance of a galactose, deficiency of Lapp-lactase and glyukozo-galaktozny malabsorption ¾ children’s and teenage age up to 18 years ¾ Joint intake of FDE-5 inhibitors, including tadalafit, with guanylate cyclase stimulators, such as riotsiguat as can potentially lead Medicinal interactions of Arist to development of symptomatic hypotonia has no clinically significant impact on clearance of medicines which metabolism proceeds with participation of an isoenzyme of P450 cytochrome. Results of a research confirmed that tadalafit does not inhibit and does not induce isoenzymes of CYP3A4, CYP1A2, CYP2D6, CYP2C19, CYP2E1 and CYP2C9. Influence of other substances on was tadalafit by Tadalafil generally is metabolized with CYP3A4 enzyme participation. Selection CYP3A4 inhibitor ketokonazol at reception in a dose of 400 mg a day increases AUC of a tadalafil after its single dose by 312%, increases the maximum concentration in blood plasma by 22%, and in a dose of 200 mg a day – for 107% and 15% respectively. Ritonavir (CYP3A4, 2S9, 2S19 and 2D6 inhibitor) in a dose of 200 mg 2 times a day increases AUC of a tadalafil after single dose by 124%, without changing the maximum concentration in blood. In spite of the fact that specific interactions were not studied, it is possible to assume that such inhibitors of proteases as sakvinavir and also CYP3A4 inhibitors, such as erythromycin and itrakonazol, increase the level of a tadalafil in blood plasma. CYP3A4 inductors For tablets on 20 mg: the selection inductor CYP3A4 rifampicin (600 mg a day) – reduces the size AUC at single use of a tadalafil by 88% and the maximum concentration – for 46% in comparison with AUC values and the maximum concentration only for one tadalafil. It is possible to expect that simultaneous use of other inductors CYP3A4 will also promote decrease in concentration of a tadalafil in blood plasma. Influence of a tadalafil on other medicines the Antihypertensive drugs Tadalafil possesses systemic vazodilatiruyushchy action which can exponentiate hypotensive effect of antihypertensive drugs. Besides, at the patients with badly controlled hypertensia taking at the same time several hypotensive drugs, perhaps more considerable decrease in the ABP. At most of patients the decrease in the ABP is not followed by hypotension symptoms. To the persons receiving treatment by antihypertensive drugs and accepting tadalafit, the corresponding clinical recommendations have to be made. Blockers of α-adrenoceptors significant decrease in the ABP at the patients accepting at the same time is not revealed tadalafit also a selection blocker α1-адренорецепторов tamsulozin. At use of a tadalafil for the healthy volunteers accepting a blocker α1-адренорецепторов docsazozin in a dose of 4-8 mg a day noted strengthening of hypotensive action. At some patients noted dizziness. Tadalafil alcohol did not affect concentration of ethanol, and ethanol did not affect concentration of a tadalafil. Against the background of intake of ethanol in high doses (0.7 g/kg of body weight) the concomitant use of a tadalafil did not lead to significant decrease in the ABP. At some patients noted postural dizziness and orthostatic hypotension. Use of a tadalafil against the background of ethanol in lower doses (0.6 g/kg) did not cause development of arterial hypotension, and dizziness was revealed with the same frequency, as at intake of only one alcohol. H2 antagonists Increase rn in a stomach as a result of use of a blocker of H2 receptors of a nizatidin did not influence pharmacokinetics of a tadalafil. Antacids (magnesium aluminum hydroxide hydroxide) the Concomitant use of antacids (hydroxide aluminum hydroxide magnesium) with tadalafily reduces the speed of its absorption without change of exposure of AUC of a tadalafil. Tadalafil acetylsalicylic acid does not increase bleeding duration against the background of intake of acetylsalicylic acid. Tadalafil warfarin has no clinically significant impact on pharmacokinetics of S-warfarin or R-warfarin and does not influence the prothrombin time induced by warfarin. Tadalafil theophylline does not render clinically significant effect on pharmacokinetics or a pharmacodynamics of theophylline. Incompatibility Tadalafil is contraindicated to the patients applying organic nitrates in any dosage form. The special instructions Drug Arista it is not intended for use for women! Diagnosis of erectile dysfunction includes identification of a potential basic reason, the corresponding medical examination and definition of tactics of treatment. The sexual activity has potential risk for patients with cardiovascular diseases. Therefore treatment of erectile dysfunction, including. the drug Arista, it is not necessary to carry out at men with such heart diseases in which the sexual activity is not recommended. There are messages about emergence of a priapism at use of FDE-5 inhibitors, including tadalafit. Patients have to be informed on need of the immediate request for medical care in case of the erection proceeding 4 hours and more. Untimely treatment of a priapism leads to damage of tissues of penis therefore there can come irreversible impotence. Safety and efficiency of a combination of the drug Arista with other types of treatment of disturbances were not studied. Therefore use of similar combinations is not recommended. Tadalafil (as well as other ingib
of Aura of FDE-5) has system vasodilating properties that can lead to tranzitorny decrease in the ABP. Before prescribing of the drug Arista the doctors have to consider carefully a question whether patients with cardiovascular diseases will be exposed to undesirable influence due to such vasodilating effects. Not arterial front ischemic optical neuropathy (NAPION) is a sight cause of infringement, including total loss of sight. There are rare messages about cases of development of NAPION, on time of FDE-5 inhibitors connected with reception. Now it is impossible to define whether there is direct link between development of NAPION and intake of FDE-5 inhibitors or other factors. Doctors have to recommend to patients to stop reception of a tadalafil in case of sudden loss of sight and to ask for medical care. Doctors also have to tell patients that at the people who transferred NAPION the risk of repeated development of NAPION is increased. The efficiency of the drug Arista at the patients who underwent surgery on bodies of a small pelvis or the radical neuropreserving prostatectomy is unknown. Use in pediatrics Drug is not intended for use for children and teenagers aged up to 18 years. Pregnancy and a lactation Drug is not intended for use for women. Fertility At some men the decrease in concentration of spermatozoa was noted. Features of influence of medicine on ability to run the vehicle or potentially dangerous mechanisms In spite of the fact that the frequency of developing of dizziness against the background of placebo and Arista is identical, during treatment it is necessary to be careful when driving motor transport and occupations other potentially dangerous types of activity demanding the increased concentration of attention and speed of psychomotor reactions. Overdose Symptoms: at single use for healthy faces of a tadalafil in a dose up to 500 mg and patients with erectile dysfunction – repeatedly up to 100 mg a day – side effects were the same, as well as at use in lower doses. Treatment: in case of overdose it is necessary to carry out standard symptomatic treatment. At a hemodialysis tadalafit it is removed slightly. A form of release and packing On 4 tablets in blister strip packaging from a film of polyvinylchloride and aluminum foil. On 1 blister strip packaging together with the instruction for medical use place in a cardboard box. To Store storage conditions in the place protected from moisture at a temperature not above 25 °C. To store out of children’s reach! A period of storage 3 years of date of production. Not to apply after an expiration date.