Hard and Strong Very Hard drug for potency. "Black pills for men sv" Tivicay - official instructions for use

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Potency stimulator Very Hard is called "eastern viagra" - its formula was created according to ancient Chinese recipes. This drug is produced by the Hong Kong-Tianlong Institute of Biopharmacolgy, for its production only natural ingredients are used - bioactive substances obtained from medicinal Tibetan herbs and the genitals of large animals.

Indications for use

The drug Solid and Strong is designed for men who want to improve their sexual performance and make intimate life more fulfilling. The tool is recommended to be taken when:

• low libido;
• erectile dysfunction;
• impotence;
• early ejaculation;
• qualitative and quantitative disorders of spermatogenesis;
• underdevelopment of the penis.

The composition and action of the components

Each Very Hard tablet contains extracts of:

• fungus Ophiocordyceps sinensis (cordyceps Tianshi) - its effect on the body is similar to ginseng;
• saffron Gur-gum - the flowers of this Tibetan plant have tonic properties, promote blood flow to the cavernous bodies of the penis;
• ragwort Senecio - the plant contains alkaloids that have a powerful sexually stimulating effect.

The composition of the bioadditive also includes extracts of animal tissues: the penis of the antler deer "Lubian", the testicle of the Tibetan bull Bos mutus, as well as seahorse powder. They serve as rich sources of testosterone, are powerful natural aphrodisiacs and have a positive effect on all organs of the male reproductive system.

Instruction

If the dietary supplement Hard and Strong is used as a potency stimulant, take 1 tablet half an hour before sexual contact. You can drink water or another drink, low-alcohol drinks are also not prohibited. The effect of the drug can last up to a day, a stable erection will occur every time you are aroused.

For the prevention of tablets Hard and strong, it is recommended to take 1 tablet at bedtime 2-3 times a week. The course of treatment is 1-2 months. Judging by the reviews, this tool does not have side effects. In very rare cases, an allergy to any component of the drug may occur. It can be taken by men at any age, and those with diseases such as hypertension or diabetes. A direct contraindication to taking dietary supplements Hard and strong is considered only a minor age. It is not recommended to combine taking Bos mutus with other means of increasing potency.

Release form and storage conditions

Bos mutus is available in 2g tablets packed in blister packs of 10. Tablets are black, drop-shaped, on one side the inscription SV is squeezed out. Store the opened package in a dark, dry place out of the reach of children.

And also YOU ​​can purchase others to increase potency.

Preparation Very Hard Hard and Strong for potency will allow you not to worry about a stable erection and will give you the opportunity to again spend sleepless nights full of bliss. Often, men are afraid of side effects in the form of headaches, indigestion, flushing to the face, nasal congestion, etc. Studies conducted by the Hong Kong-Tianlong Institute of Biological Pharmacology have shown that this remedy is devoid of such shortcomings. Moreover, it provides an increase in the duration of sexual intercourse, has a long (up to 180 hours) mild but powerful stimulating effect on the sexual function of a man, and also does not cause addiction and is safe for health.

Indications for use:

• erectile disfunction;
• impotence, weakening of sexual desire;
• premature ejaculation (spermatorrhea);
• signs of male diseases: weakness in the limbs, pain in the lower back and knees, tinnitus, frequent nighttime urination, sweating during sleep;
• adenoma and prostatitis;
• small size of the penis.

Compound: Chinese Cordyceps, Senecio, Tibetan saffron, seahorse, deer penis, Tibetan yak testicle, etc.

Very Hard Hard and Strong instructions for use:

• for sex: take 1 tablet Very Hard Hard and Strong for potency 20-30 minutes before intercourse with warm water. To speed up and improve the action, you can chew. In case the erection does not go away, drink cold water to relieve the effect;
• for the prevention of male diseases and penis growth, take 1 tablet 30 minutes before bedtime 1 time in three days.

Contraindications: do not use more than 1 piece per 24 hours, should not be taken by minors, with individual intolerance, do not combine with other means to increase potency.

Storage: in a dry, dark place out of the reach of children.

Release form: 10 black Teardrop-shaped tablets with embossed letters SV of 2000 mg. Packing weight 20 grams.

Production: Hong Kong Tianlong Institute of Biological Pharmacology, China.

Dietary supplement is not a medicine. Before use, it is recommended to consult a specialist.

Leave about Very Hard Hard and Strong reviews!

A modern man is in constant stress, lack of sleep, working 10-12 hours a day. The situation is aggravated by eternal traffic jams and many other reasons, which inevitably affects the state of health. Such a misfortune as erectile dysfunction has already added to the list of the most common chronic diseases.

If such sadness has befallen you, do not rush to tear your hair on your head and wring your hands catastrophically. We will tell you how to restore a potency that has fallen ill with the help of a dietary supplement in tablets Very Hard - “Hard and strong” to increase the potency of men, where to buy it and at what price, reviews about the drug, description and application.

In contact with

What is "Hard and Strong"

The drug Very Hard was invented for a complete recovery. Strictly speaking, it works to upgrade the two main pillars of male power: erection (capacity) and libido (desire).

The product belongs to the class of dietary supplements and is available in the form of oblong black tablets. Each pill is engraved with "SV". Let's admit course and one-time reception.

The composition of the drug

The bioadditive contains the strongest composition invented by Chinese healers.

The building blocks of the stimulating formula are as follows:

• Tibetan saffron- a source of vitamins, minerals can equalize testosterone, improve the quality of seminal fluid. There is a rejuvenating effect and a positive effect on brain activity;

• sea ​​Horse- gives strength for sexual marathons, gives brightness of sensations, has a general strengthening effect, improves the functioning of the heart, blood vessels, and the functioning of the organs of vision;

• Tibetan yak testicles, deer penis- a very strong chip from Chinese medicine. Both components give the body a lot of amino acids, normalize testosterone, revitalize libido, sexual stamina;

• senecio- the plant moves the erection off the ground, strengthens the defenses;

• Chinese caterpillar mushroom Cordyceps works just as well as Viagra. It appeals to the bloodstream, serves in the treatment and prevention of any erectile disorders. There is a restoration of the quality of seminal fluid, improvement of the prostate gland.

Dietary supplement properties

The good news is that the composition is safe for the body, does not cause addiction, dependence. It provides gentle yet powerful stimulation to revive male sexual function.

A whole range of useful properties:

• increased blood flow - there is a powerful stimulation of complete blood filling of the cavernous bodies. This is the key to a powerful erection and a visual increase in size;
• strengthening immunity, general physical health;
• removal of inflammatory processes in the pelvic area;
• improving the functioning of the liver, kidneys;
• delayed premature ejaculation;
• stabilization of the hormonal background;
• improving the production and quality of seminal fluid.

The action of the pills lasts up to 72 hours, coitus is extended up to 180 minutes.

In what cases does it help?

The drug will help with various failures of male sexual health.

Iron reason for admission:

• weakened sexual desire, asexuality;
• erectile dysfunction, erectile dysfunction;
• impotence;
• spermatorrhea - a condition characterized by premature ejaculation;
• symptoms of male diseases - sweating during sleep, frequent nighttime urination, tinnitus, pain in the knees, lower back, weakness in the arms and legs.

There is an excellent therapeutic effect in diseases of the prostate gland. This is an ideal solution for comrades at a respectable age. Dosage adjustment for men over 55 years of age is not required.

Instructions for use

The Chinese drug like Viagra - Hard and strong - the instructions for use are extremely simple. For a rapid surge of male strength and a strong erection, eat 1 pill 20-30 minutes before intercourse. Drink warm, brackish water. Such a kunshtuk will help to retain the maximum of useful substances in the body. For convenience, the tablet can be crushed. The maximum daily dose - 1 piece.

The dietary supplement is calmly used against the background of diabetes, hypertension, heart disease.

To cure early ejaculation, prospermia, urogenital disorders, impotence, take 1 pill every 3 days. The main thing is not to despair, not to be sad, but to show firmness and perseverance! Keep the course intake for at least 3 months. Such a period will serve in the overall strengthening of the body, will start the motor of potency.

What results to expect

The latest results of the use of bioadditives are worthy of all praise. Without juggling and other tricks, the formula helps 91% of men. The return of the lost potency, the general strengthening of the state of health are achieved after a course of administration.

One-time use helps 85-87% of comrades. This approach stimulates libido, adjusts sensations to a new, bright level, adds endurance and strength.

Price

One package contains 10 pills in a vacuum blister. The price of the box is from 990 rubles. A more modest cost should alert and suggest that you have a fake in front of you.

Reviews

We've compiled some real life supplement reviews from living men and members of the medical community.

Doctors' opinion

Urologists reported that a joint European-American study revealed a sad picture: in the world, almost one in three comrades over the age of 30 suffers from erectile dysfunction. Of course, with age, the figure becomes even higher. Impotence today is a real disease of civilization.

The good news is that male sexual power can be restored. Doctors explain that herbal medicines help a lot in this. They stated that the specific preparation "Hard and Strong" is balanced in composition. With a course intake, it will eliminate the causes of erectile disorders. Potency will be restored naturally. But, in case of serious health problems, it is better to visit a doctor first.

Reviews of men - buyers of the drug

Oleg, 52 years old, Moscow

A busy schedule and emotional overload simply knocked me out of my strength. All this affected the sexual function. I decided to drink synthetics at the last moment, at first I thought to go through herbal preparations.

Among all dietary supplements, I liked “Hard and strong” more. I took the course, strictly according to the instructions, now I'm normal on all fronts.

Igor, 45 years old, Voronezh

"Hard and strong" is my longtime favorite. The bioadditive pleases with the absence of side effects, mild action, reasonable price and excellent quality.

The pills return a strong, firm erection, instilling confidence before each sexual intercourse. I recommend!

Where is it profitable to buy the original

To keep a stone erection even in retirement, you need to get the original. Only a real product from the manufacturer will give the body the declared complex of useful properties. This option can be found in an online pharmacy for adults. The trusted site can be visited here.

Contraindications, harm and side effects

Captain Evidence suggests that the main contraindication to use is individual intolerance to the components. We advise you to consult a urologist in the presence of inflammation, injuries below the waist. If there is insomnia, excessive nervous excitability, hypertension, atherosclerosis, you should consult with a therapist.

All the noted symptoms occur against the background of an overdose and disappear after the abolition of the pills and the use of the enterosorbent.

Dietary supplement Solid and strong has successfully passed clinical trials at the Hong Kong-Tyaluan Institute of Biotechnology for harm and contraindications. Experiments on living men have shown that it does not cause such common adverse reactions as indigestion, headache, nasal congestion, flushing of the face, heart palpitations.

Compatibility with other drugs and alcohol

We will tell you how to properly combine pills with everything else that enters the body of a true inhabitant of a modern metropolis.

Compatibility standards:

• "Hard and strong" is friendly with a little alcohol. We recommend a glass of wine or a glass of vodka - these are the things that are useful for an erection (in a dosed form). Give up cognac, whiskey, brandy;
• the drug can be taken with food - food should be light and low-fat. Give fast food, fried potatoes and pork knuckle to the enemy;
• cannot be combined with others and for erection stimulants - you will run into a lot of side effects and an unpleasant long-term erection, which you will not get rid of for 3 hours. But there is an excellent interaction with other medications. The product does not provoke an increase in the concentration of active components in the blood and does not reduce their effectiveness.

If the pills cause multiple erections without finishing discharge, you should drink at least 3 liters of boiled water (not immediately).

Chinese drugs of a similar effect

We have found several competing comrades that can become a worthy alternative to the Hard and Strong dietary supplement.

Conclusion

In the fight against erectile dysfunction, you can not give up! "Hard and strong" is specially designed for men who consciously approach the solution of intimate problems. Take the drug to your asset, it will give you a readiness for intimacy and the same stable self-confidence.

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Catad_pgroup Antivirals for HIV

Tivicay - official instructions for use

Registration number:

LP 002536 - 210617

Tradename:

Tivicay ® / Tivicay ®

International non-proprietary name:

dolutegravir / dolutegravir.

Dosage form:

film-coated tablets.

COMPOSITION

Each tablet contains:

DESCRIPTION

Yellow, round, biconvex tablets, debossed with "SV 572" on one side and "50" on the other side.

PHARMACOTHERAPEUTIC GROUP

Antiviral (HIV) agent.

CodeATH: J05AX12.

PHARMACOLOGICAL PROPERTIES

Pharmacodynamics

Mechanism of action

Dolutegravir inhibits HIV integrase by binding to the active site of the integrase and blocking the strand transfer step during retroviral deoxyribonucleic acid (DNA) integration, which is required for the HIV replication cycle. Strand transfer biochemical assays using purified HIV-1 integrase and pretreated DNA substrate gave IC50 values ​​(50% inhibition of replication) of 2.7 nM and 12.6 nM. In vitro dolutegravir slowly dissociates from the active site of the wild-type DNA-integrase complex (t1/2 71 hours).

Pharmacodynamic effects

In a randomized dose-optimal study in HIV-1 infected patients treated with dolutegravir (ING111521) monotherapy, there was a rapid and dose-dependent antiviral effect, with a mean decrease in HIV-1 RNA at day 11 from baseline of 1.5 , 2.0 and 2.5 log10 for dolutegravir 2mg, 10mg and 50mg once daily, respectively. This antiviral response was maintained for 3-4 days after the last dose in the 50 mg dolutegravir group.

Antiviral activity in cell culture

In peripheral blood mononuclear cells (PBMCs) infected with HIV-1 Bal strain or HIV-1 strain NL432, IC values ​​of 0.51 nM 0.53 nM were obtained for dolutegravir. respectively. In MT-4 cells infected with HIV-1 strain 1MB and incubated with dolutegravir for 4 or 5 days, IC50s of 0.71 and 2.1 nM were obtained.

In a viral integrase sensitivity analysis using the integrase coding region from 13 clinically distinct subtype B isolates, dolutegravir demonstrated antiviral activity similar to that against laboratory strains, with a mean IC50 of 0.52 nM. In a PBMC analysis of a panel of 24 HIV-1 clinical isolates [group M (subtypes A, B. C, D, E, F, and G) and group O] and 3 HIV-2 clinical isolates, the geometric mean IC50 was 0.20 nM, and IC50 values ​​ranged from 0.02 to 2.14 nM for HIV-1, while for HIV-2 isolates, the geometric mean IC50 was 0.18 nM. and IC50 values ​​ranged from 0.09 to 0.61 nM.

Antiviral activity in combination with other antiviral drugs

None of the drugs with typical antiviral activity against HIV showed antagonism to dolutegravir [ in vitro evaluations were performed in combination with stavudine, abacavir, efavirenz, nevirapine, lopinavir, amprenavir, enfuvirtide, maraviroc, adefovir and raltegravir, selected in a checkerboard pattern). In addition, antivirals without typical HIV activity (ribavirin) had no apparent effect on the activity of dolutegravir.

Influence blood serum and human serum proteins

Research in vitro confirmed a 75-fold change (CI) in the IC50 of dolutegravir in the presence of 100% human serum (by extrapolation), and the IC90 adjusted for protein binding (PA-IC90) in PBMC was 64ng/mL.

The trough concentration of dolutegravir after a single dose of 50 mg in patients not previously treated with imtegrase inhibitors (InIs) was 1.20 mcg/mL, 9-fold higher than the established PA-IC90.

Sustainabilityin vitro

Wild type HIV-1 isolates: during the 112-day passage of strain IIIB, no viruses with high resistance to dolutegravir were detected. the maximum 4.1-fold change was observed in passaged groups of resistant viruses With substitutions SI53Y and S153F in conserved positions of the integrase gene. Passage of the HIV-1 wild-type strain HL432 in the presence of dolutegravir resulted in the selection of the 92Q substitution (virus passage group with CI = 3.1) and G193B (virus passage group with CI 3.2) at day 56. Additional passage of subtypes B. C and A/G of the wild-type virus in the presence of dolutegravir resulted in the selection of R263K. Gl 18R and S153T.

Antiviral activity against resistant strains: strains resistant to reverse transcriptase inhibitors (RTIs) and protease inhibitors (IIs): Aolutegravir showed similar activity against 2 non-nucleoside (HH)-RTI-resistant, 3 nucleoside (N)-RIT-resistant and 2 PI-resistant mutant clones of HIV- 1 (1 triple and 1 sixfold resistant) compared to wild strain.

HIV-1 strains resistant to INI: 60 HIV-1 mutant isolates resistant to INI (28 with one substitution and 32 with 2 or more substitutions) were generated from wild-type virus BL432 by site-directed mutagenesis. Dolutegravir has demonstrated antiviral activity (susceptibility) against HIV with CI< 5 в отношении 27 из 8 мутантпых вирусов, устойчивых к ИнИ с одной заменой, в том числе T66A/I/K. E92Q/V, 43C/M/R. Q148H/K/R и N15511, в то время как для ралтегравира и элвитегравира сгивность проявилась в отношении 17/28 и 11/21 тестируемых мутантпых вирусов с КИ < 5. соответственно. Кроме того, из 32 мутантных вирусов, устойчивых к ИнИ с 2 или олее заменами, 23 из 32 продемонстрировали КИ < 5 для долутегравира по сравнению с И < 5 для 4 из 32 для ралтегравира и КИ < 5 для 2 из 25 тестируемых вирусов для титегравира.

InI-resistant HIV-2 strains: the viruses were obtained by site-directed mutagenesis of HIV-2 isolates isolated from HIV-2 infected patients who received raltegravir and who showed virological treatment failure. In general, CIs in HIV-2 were similar to CIs in HIV-1, which were observed with a similar set of mutations. The CI of dolutegravir was< 5 против 4 вирусов ВИЧ-2 (S163D, G140A/Q148R, A153G/N155H/S163G и I292Q/T97A/N155H/S163D); для Е92Q/N155II КИ долутегравира составило 8,5, а для G140S/QI48R КИ долутегравира составило 17. Долутегравир, ралтегравир и элвитегравир проявили одинаковую активность против ВИЧ-2 с сайт-направленной мутацией с SI63D, как и в отношении дикого типа, а для остальных мутантных вирусов ВИЧ-2 диапазоны КИ ралтегравира составили 6,4-420, а диапазоны КИ элвитегравира составили 22-640.

Clinical isolates in patients with virological treatment failureraltegravir: Thirty clinical isolates with genotypic and phenotypic resistance to raltegravir (median CI >81) were tested for susceptibility to olutegravir (median CI 1.5) by Monogram Biosciences PlienoSense analysis. The median CI of dolutegravir for isolates with substitutions at positions 140S-I-Q148II was 3.75: G140S + Q148R - 13.3: T97A + Y143R - 1.05 and 15511 - 1.37. 705 raltegravir-resistant isolates from raltegravir-treated patients were tested for susceptibility to dolutegravir by Monogram Biosciences PhenoSense analysis. Dolutegravir showed CI<10 в отношении 93.9% из 705 клинических изолятов, при этом у 16 (9%) из 184 изолятов с заменой QI48 + 1 с резистентностью к ИнИ и 25 (27%) из 92 клинических изолятов с заменой Q148 + >2 with resistance to InI, more than 10-fold change was observed.

Sustainability in vivo: patients who did not take INI

There were no mutations in INI resistance or treatment-associated resistance to nucleoside reverse transcriptase inhibitors (NRTIs) backbone therapy in previously untreated patients treated with dolutegravir 50 mg once daily (SPRING-1, SPRING-2, SINGLE and FLAMINGO studies). ). In the SAILINGy study of dolutegravir-naïve patients (n = 354 in the delutegravir group), treatment-related substitutions in integrase were observed at week 48 in 4 of 17 patients with virological failure receiving dolutegravir. 2 out of 4 patients had a unique R263K substitution in the integrase gene with a maximum CI of 1.93, 1 patient had a V151V/I integrase polymorphism with a maximum FC of 0.92, and 1 patient already had integrase mutations initially and was presumed to be previously received InI or was infected with InI-resistant virus.

The VIKING-3 trial investigated dolutegravir (plus optimized backbone therapy) in patients with pre-existing INI resistance. Up to week 24, 36 of 183 patients had protocol-defined virologic failure (PDVF). Of these, 32 patients had paired data for baseline and PDVF resistance for analysis. and 17/32 (53%) had treatment-associated mutations, the following treatment-associated mutations or combinations of mutations were observed: L74L/M (n=1), E92Q (n=2), T97A (n=9), E138K /A/T (n = 8), G140S (n = 2), Y143H (n = 1). S147G (n=l), Q148H/K/R (n = 4). N155II (n=1) and E157E/Q (n=1). Fourteen of 17 patients with treatment-associated viral mutations either had C148 mutation at baseline or history. Five other patients developed PDVF between weeks 24 and 48, and 2 of these 5 patients had treatment-induced mutations. Marked mutations that arose during treatment, or combinations of mutations, were L74I (n = 1), M55H (n = 2).

The VIKING-4 study examined dolutegravir (plus optimized background therapy) in 30 patients with primary genotypic resistance to InI at screening. The mutations that occurred during treatment were consistent with those observed in the VIKING-3 study.

In a randomized, crossover, placebo-controlled clinical trial, 42 healthy volunteers received a single dose of placebo, 250 mg suspension of dolutegravir (approximately 3 times the exposure of the 50 mg once daily dose at steady state) and moxifloxacin (400 mg, active control) at random. okay. Dolutegravir did not prolong the corrected interval (QTc) within 24 hours of dosing. After adjustment for baseline ECG and placebo, the maximum mean change in QTc based on Frederick's formula (QTcF) correction was 1.99 msec (upper limit of 1-sided 95% confidence interval - 4.53 msec).

Effect on kidney function

The effects of dolutegravir on serum creatinine clearance (CC), sponge filtration rate (GFR) in the iogxol test, and effective renal plasma flow (EPF) in the paraaminohypyurate test were evaluated in an open, randomized, placebo-controlled, 3-group, 3-arm study of 37 healthy volunteers who received dolutegravir 50 mg once daily (n=12), 50 mg twice daily (n=13) or placebo once daily (n=12) for 14 days. There was a moderate decrease in CC with dolutegravir during the first week of treatment, consistent with the decrease observed in clinical studies. Both doses of dolutegravir had no significant effect on GFR or EPP, these data are supported by studies in vitro, which suggest that the small increases in creatinine levels observed in clinical studies are caused by non-pathological inhibition of the organic cation transporter (OCT2) in the proximal renal tubule, which causes tubular secretion of creatinine.

Pharmacokinetics

The pharmacokinetics of dolutegravir in healthy volunteers and HIV-infected patients is the same. The pharmacokinetic variability of dolutegravir was low to moderate. In Phase 1 studies in healthy volunteers, the coefficient of variation (KB) among participants for the area under the concentration-time pharmacokinetic curve (AUC) and for the maximum concentration (Cmax) ranged from 20 to 40%, and the concentration at the end of the dosing interval ( C max) - from 30 to 65%. Inter-subject variability in the pharmacokinetics of dolutegravir between participants was greater in HIV-infected patients than in healthy volunteers. The individual variability in pharmacokinetic parameters was lower than the inter-individual variability.

Suction

Dolutegravir is rapidly absorbed after oral administration, with a median time to peak concentration (Tmax) following a tablet dose of 2-3 hours. The linearity of the pharmacokinetics of dolutegravir is dose and drug dependent. Following oral administration, dolutegravir tablet form generally exhibited non-linear pharmacokinetics, with a less than dose-dependent increase in plasma exposure from 2 to 100 mg, however, increases in dolutegravir exposure were dose proportional from 25 mg to 50 mg.

Dolutegravir can be taken with or without food. Food increases the extent and decreases the rate of absorption of dolutegravir. The bioavailability of dolutegravir depends on the content of the diet: with a meal with a low, moderate and high fat content (AUQ 0-∞), dolutegravir increased by 33%, 41% and 66%, Cmax increased by 46%, 52% and 67%, Tmax was prolonged up to 3, 4 and 5 hours compared to 2 hours when taken on an empty stomach, respectively. These increases are not of clinical significance. The absolute bioavailability of dolutegravir has not been established.

Distribution

According to the data received in vitro, dolutegravir is highly (99.3%) bound to human plasma proteins. The apparent volume of distribution (after oral administration in the form of a suspension, Vd / F) is approximately 12.5 liters. Plasma protein binding of dolutegravir was independent of concentration. The ratios of the total concentration of the radioactively labeled drug in blood and plasma were 0.441-0.535, which indicates the minimum connection of the radioactively labeled drug with the cellular components of the blood. The free fraction of dolutegravir in plasma is approximately 0.2-1.1% in healthy volunteers, approximately 0.4-0.5% in patients with moderate hepatic insufficiency, 0.8-1.0% in patients with severe renal insufficiency, and 0.5% in patients infected with HIV-1.

Dolutegravir passes into the cerebrospinal fluid (CSF). In 12 previously untreated patients treated with dolutegravir and abacavir/lamivudine II for 16 weeks, mean CSF concentrations of dolutegravir were 15.4 ng/mL at week 2 and 12.6 ng/mL at week 16, with a range of 3 .7 to 23.2 ng/mL (comparable to
bound plasma concentration). The ratio of dolutegravir concentration in CSF to plasma concentration ranged from 0.11% to 2.04%. Dolugegravir CSF concentrations exceeded the IC50, confirming a median decrease in CSF HIV-1 RNA concentration from baseline of 2.2 log tq after 2 weeks of therapy and 3.4 log after 16 weeks of therapy (see subsection Pharmacodynamics).

Delutegravir is found in the male and female reproductive tract. AUC in cervico-vaginal fluid, cervical and vaginal tissues was 6-10% of that in plasma at steady state. AUC in seminal fluid was 7%, and in the tissues of the rectum - 17% of that in blood plasma at equilibrium concentration.

Metabolism

Dolutegravir is primarily metabolized by uridine diphosphate-glucuronosyltransferase UDP-GT1A1 with a minor component of the CYP3A isoenzyme (9.7% of the total administered dose in a human mass balance study). Dolutegravir is the main compound circulating in blood plasma, unchanged excreted through the night (< 1 % дозы). 53 % общей дозы, принятой внугрь, выводится в неизмененном виде через кишечник. Неизвестно, объясняется это неполным всасыванием лекарственного препарата или выведением с желчью глюкуронидного конъюгата, который дальше может распадаться до образования родственных соединений в просвете кишечника. 31 % общей дозы, принятой внутрь, выводится через почки в форме эфира глюкуронида долугегравира (18.9% общей дозы). N-деалкилированного метаболита (3,6 % общей дозы) и метаболита, образованного путем с кисления бензилового углерода (3.0 % общей дозы).

breeding

The terminal half-life of dolugegravir is approximately 14 hours and the apparent clearance (CL/F) is 0.56 L/h.

Special patient groups

Children

In a pediatric study including 23 HIV-1-infected children and adolescents aged 12 to 18 years who had previously received antiretroviral treatment, pharmacokinetic data for dolugegravir in 10 children showed that a daily dose of 50 mg of dolutegravir resulted in the same exposure of dolugegravir in children and adolescents, as in adults who received 50 mg of dolugegravir once a day.

Pharmacokinetic parameters in children (n=10)

a - One patient weighing 37 kg received dolutegravir 35 mg once daily.

Elderly patients

A population pharmacokinetic analysis of dolutsgravir using data from adults infected with HIV-1 showed no clinically significant effect of age on dolutegravir exposure.

There are limited data on the pharmacokinetics of dolutegravir in patients over 65 years of age.

Renal clearance of unchanged drug is a minor route of elimination for dolutegravir. The pharmacokinetics of dolutegravir was studied in patients with severe renal impairment (CK< 30 мл/мин). Не наблюдалось клинически значимых фармакокинетических различий между пациентами с нарушением функции почек тяжелой степени (КК < 30 мл/мин) и з хоровыми добровольцами. Пациентам с нарушением функции почек коррекции дозы не тэебуется. Долутегравир не исследовался в группе пациентов, находящихся на диализе, тгм не менее, различия в фармакокинетике не ожидаются.

Dolutegravir is metabolized and eliminated primarily by the liver. In a study comparing 8 patients with moderate hepatic impairment (Child-Pyo class B) and 8 healthy adult volunteers, exposure to a 50 mg vase dose of dolutegravir was similar between the two groups. Patients with mild to moderate hepatic impairment do not require yuza correction. The effect of severe hepatic impairment on the pharmacokinetics of dolutegravir has not been studied.

Polymorphism of drug-metabolizing enzymes

There is no evidence that common drug-metabolizing enzyme polymorphisms alter the pharmacokinetics of dolutegravir to a clinically meaningful extent. In a meta-analysis using pharmacogenomic samples. obtained in clinical studies involving healthy volunteers in patients with UDP-GT1A1 genotypes (n = 7). who had a poor metabolism of dolutegravir, the clearance of dolutegravir was reduced by 32%. a AUC was 46% higher compared with patients with genotypes associated with normal metabolism via UDP-GT1A1 (n = 41). Polymorphisms of CYP3A4, CYP3A5 and NR112 isoenzymes were not associated with differences in the pharmacokinetics of dolutsfavir.

Based on data obtained in a study involving healthy volunteers (men n = 17, women n = 24). dolutegravir exposure was found to be slightly higher in women (by about 20%) than in men. A population-based pharmacokinetic analysis using pooled pharmacokinetic data from Phase IIb and Phase III adult clinical trials showed no clinically significant effect of gender on dolutegravir exposure.

Race

A population pharmacokinetic analysis using pooled pharmacokinetic data from Phase IIb and Phase III adult clinical trials showed no clinically relevant effect of race on dolutegravir exposure. The pharmacokinetics of dolutegravir after a single oral dose in Japan have been shown to be similar to those in Western populations (USA).

Co-infection with HIV and viral hepatitis B or C

Population pharmacokinetic analysis showed that hepatitis C virus co-infection had no clinically significant effect on dolutegravir exposure. Data on patients with hepatitis B coinfection are limited.

INDICATIONS FOR USE

Treatment of HIV-1 infection in adults and children from 12 years of age and weighing 40 kg or more as part of combination antiretroviral therapy (APT).

CONTRAINDICATIONS

Hypersensitivity to dolutegravir or any other concomitant of the drug. Simultaneous reception with dofetilide or pelsicainide, children under 12 years of age and weighing less than 40 kg.

CAREFULLY

Severe liver failure (Child-Pugh class C);

With simultaneous use with drugs (prescription and non-prescription) that can change the effect of the drug Tivicay®, or drugs, the effect of which may change under the influence of Tivicay® drug.

USE IN PREGNANCY AND DURING BREASTFEEDING, EFFECTS ON FERTILITY

Fertility

There are no data on the effect of Tivicay on the ability to conceive in men and women. Animal studies have shown no effect of dolutegravir on fertility in males or females.

Pregnancy

There are no adequate and well-controlled studies of Tivicay in pregnant women. The effect of Tivicay on pregnancy in women is unknown. In animal reproductive toxicity studies, dolutegravir has been shown to cross the placenta. Tivicay should only be used during pregnancy if the expected benefit to the mother outweighs the potential risk to the fetus.

breastfeeding period

Based on animal data, dolutegravir is expected to be excreted in human breast milk, although this has not been confirmed in humans.

METHOD OF APPLICATION AND DOSES

Therapy with Tivicay must be carried out by a physician experienced in the treatment of HIV infection.

Tivicay can be taken with or without food.

adults

HIV-1 infected patients without InI resistance

When used simultaneously with efavirenz, nevirapine, rifampicin or tmpranavir in combination with ritonavir, the recommended dose of Tivicay in this category of patients should be 50 mg 2 times a day.

HIV-1 infected patients with InI resistance (documented or clinically suspected)

Missed medication

If a patient misses a dose of Tivicay*, they should take the missed dose as soon as possible if the next dose is at least 4 hours away. If less than 4 hours remain before the next dose, the patient should not take the missed dose, and it is necessary to resume taking the drug according to the regimen.

Children aged 12 to 18 and weighing 40 kg or more

Special patient groups

Children under 12 years of age and weighing less than 40 kg

There are insufficient safety and efficacy data to recommend a dose of Tivica in children under 12 years of age or weighing less than 40 kg.

Elderly patients

Data on the use of Tivicay in patients aged 65 years and older are limited. However, there are no data on the need for dose adjustment in elderly patients. - "Special groups of patients").

Patients with impaired renal function

Patients with mild, moderate or severe renal impairment (QC<30 мл/мин, не на диализе) не требуется коррекция дозы. Отсутствуют данные для пациентов, находящихся на диализе, но различий в фармакокинетике в данной популяции не ожидается (see section "Pharmacokinetics"- "Special groups of patients").

Patients with impaired liver function

Patients with mild or moderate hepatic impairment (Child-Pugh class A or B) do not require dose adjustment. No data available for patients with severe hepatic impairment (Child-Pyo grade C) (see section "Pharmacokinetics"- "Special groups of patients").

SIDE EFFECT

The adverse reactions presented below were established during the analysis of pooled data from Phase IIb and III clinical trials and are listed according to the damage to organs and organ systems and the frequency of occurrence. The frequency of occurrence is determined as follows: Often(≥ 1/10), often(≥ 1/100 and< 1/10), infrequently(≥ 1/1000 and< 1/100), rarely(≥ 1/10,000 and< 1/1 000) и very rarely(< 1/10 000, включая отдельные случаи).

Frequency of occurrence of undesirable reactions

Immune System Disorders

Uncommon: hypersensitivity reaction, immune reconstitution syndrome.

Mental disorders

Often: insomnia, unusual dreams, depression.

Uncommon: suicidal ideation or suicide attempt (especially in patients with depression or a history of mental illness).

Nervous System Disorders

Very common: headache; common: dizziness.

Gastrointestinal disorders

Very common: nausea, diarrhea,

Common: Vomiting, flatulence, upper abdominal pain, abdominal pain, abdominal discomfort.

Liver and biliary tract disorders

Uncommon: hepatitis.

Skin and subcutaneous tissue disorders

Often: rash, itching.

General disorders and disorders at the injection site

Often: fatigue.

Laboratory and instrumental data

Often: increased activity of alanine aminotransferase (ALT) and / or aspartate aminotransferase (ACT), creatine phosphokinase (CPK).

The safety profile was similar in the populations of previously untreated patients, treated patients (and not taking integrase inhibitors), and patients with integrase inhibitor resistance.

Description of individual side effects

Changes in laboratory parameters

During the first week of treatment with Tivicay, an increase in serum creatinine concentration was noted, which persisted for 48 weeks. The mean change in creatinine concentration at 48 weeks of therapy was 9.96 µmol/l. The increase in creatinine concentration was comparable for various background regimens. These changes are not considered clinically significant as they do not reflect changes in glomerular filtration rate.

At the time of initiation of combination antiretroviral therapy (cART) in HIV-infected patients with severe immunodeficiency, an inflammatory reaction may develop against the background of asymptomatic opportunistic infections or their residual effects. Autoimmune diseases (eg, Graves' disease) have also been reported in association with immune reconstitution, but the time of onset varied and the disease could occur many months after initiation of therapy.

Use in children

Based on limited data on use in children and adolescents aged 12 to 18 years, it can be concluded that there are no additional types of adverse reactions, in addition to the reactions that were observed in adults.

Co-infection with HIV and hepatitis B or C virus

Patients co-infected with hepatitis B and/or C virus were allowed to enter Phase III studies, provided that the results of the baseline laboratory parameters of liver function did not exceed the upper limit of normal (ULN) by more than 5 times. Overall, the safety profile in patients co-infected with hepatitis B and/or C virus was the same as in patients without coinfection with hepatitis B or C virus, despite the fact that the incidence of abnormal ACT and ALT activity was higher in the co-infected subgroup. hepatitis B and/or C virus in all treatment groups. Elevated liver enzymes consistent with immune reconstitution syndrome have been observed in some patients co-infected with hepatitis B and/or C virus at initiation of Tivicay therapy, especially in those who have discontinued hepatitis B treatment.

Post-registration data

Violationsfrom the musculoskeletal and connective tissue

Uncommon: arthralgia, myalgia.

OVERDOSE

Symptoms

Data on overdose of Tivicay are limited.

Limited experience with higher single doses (up to 250 mg in healthy volunteers) did not reveal any specific symptoms or signs other than those described in the Adverse Effects section.

Treatment

Further treatment should be carried out in accordance with clinical indications or the recommendations of the national poison control center, where applicable. There is no specific treatment for overdose with Tivicay. In case of overdose, supportive therapy and appropriate monitoring should be carried out. Due to the high plasma protein binding of dolutegravir, it is unlikely that a significant amount can be removed by dialysis.

INTERACTIONS WITH OTHER DRUGS

Effects of dolutegravir on the pharmacokinetics of other drugs

In vitro dolutegravir demonstrates no direct inhibition or weak inhibition (IC50>50 μM) of isoenzymes of the cytochrome P450 (CYP)A2 system. CYP2A6, CYP2B6. CYP2C8, CYP2C9, CYP2C19. CYP2D6 CYP3A, UDP-GT1A1 or UDP-GT2B7, or Pgp transporters. BCRP, BSEP, OATPIB1, OATP1B3, OSP, MRP2, or MRP4. In vitro dolutegravir does not induce CYP1A2, CYP2B6 or CYP3A4 isoenzymes. in vivo dolutegravir has no effect on midazolam, a measure of CYP3A4 activity. Based on these data, Tivicay is not expected to affect the pharmacokinetics of medicinal products that are substrates of these enzymes or transporters (eg, reverse transcriptase or protease inhibitors, abacavir, zidovudine, maraviroc, opioid analgesics, antidepressants, statins, azole fungicides, inhibitors proton pump, erectile dysfunction drugs, acyclovir, valaciclovir, sitagliptin, adefovir).

In drug interaction studies, dolutegravir had no clinically significant effect on the pharmacokinetics of the following drugs: tenofovir, ritonavir, methadone, efavirenz, lopinavir, atazanavir, darunavir, etravirine, fosamprenavir, rilpivirine, boceprevir, telaprsvir, daclatasvir, and oral contraceptives containing norgestimate and ethinyl stradiol .

In vitro dolutegravir inhibited the renal organic cation transporter 2 (OCT2) IC50 = 1.93 μM), the excretory transporter of various drugs and toxins (MATE) 1 (IC 50 = 6.34 μM) and MATE2-K (IC 50 = 24.8 μM). Based on dolutegravir exposure in vivo, unlikely, potential effect on transport of MATE2-K substrates in vivo. In vivo dolutegravir may increase plasma concentrations of drugs whose elimination is dependent on OCT2 or MATE1 (dofetilide, pilsicainide, or metformin) (see Table 1). In vitro dolutegravir inhibited the basolateral renal transporters: organic anion transporter (OAT) 1 (IC50 = 2.12 µM) and OAT3 (IC50 = 1.97 µM). However, dolutegravir had no significant effect on pharmacokinetics. in vivo OAT substrates tenofovir and para-aminohippurate, and thus had little ability to induce drug interactions through inhibition of CAT transporters.

Effect of other agents on the pharmacokinetics of dolutegravir

Dolutegravir is eliminated primarily by the metabolism of UDP-GT1A1. Dolutegravir is also a substrate for UDP-GT1AZ, UDP-GT1A9, CYP3A4, Pgp, and BCRP; therefore, medicinal products that induce these enzymes or transporters could theoretically reduce plasma concentrations of dolutegravr and reduce the therapeutic effect of Tivicay.

Simultaneous use of the drug Tivicay and other drugs that inhibit UDP-GT1A1, UDP-GT1AZ. UDP-GT1A9, CYP3A4 and/or Pgp may increase plasma concentrations of dolutegravir (see Table 1).

in vitro dolutegravir is not a substrate for human organic anion transport polypeptide (OATP)lBl. OATP1B3 or OCT1, therefore drugs that exclusively modulate the activity of these transporters would not be expected to affect plasma concentrations of dolutgravir.

Efavirenz, etravirine, nevirapine, rifampicin, carbamazepine and tipranavir in combination with ritonavir significantly reduced plasma concentrations of dolutegravir and therefore a dose adjustment of Tivicay to 50 mg twice daily is required. The effect of etravirine was attenuated by concomitant use of the CYP3A4 inhibitors lopinavir/ritonavir, darunavir/ritonavir, and is expected to be attenuated by atazanavir/ritonavir. Therefore, no dose adjustment of Tivicay is required when doputegravir is co-administered with etravirine and either lopinavir/ritonavir, dagunavir/ritonavir, or atazanavir/ritonavir.

Another inducer, fosampresnavir. in combination with ritonavir. reduced plasma concentrations of lutegravir ds, but dose adjustment of Tivica is not required (see Table 1). Interaction study with UDP-GT1A1 inhibitor. atazanavir did not show a clinically significant increase in dolutegravir plasma concentrations. Tenofovir, lopinavir/ritonavir, darunavir/ritonavir, rilpivirine, boceprevir, telaprevir, prednisone, rifabutin, daclatasvir, and omeprazole had no or minimal effect on the pharmacokinetics of dolutegravir, so dose adjustment of Tivicay is not required when co-administered with these medicinal products.

Interactions with individual medicinal products are presented in Table 1. Recommendations are based either on interaction studies with other medicinal products or on predicted interactions due to the expected magnitude of interactions and the potential for serious adverse events or loss of efficacy.

Abbreviations: - increase; ↓- decrease; ↔ - no significant changes; AUC is the area under the concentration-time curve, Cmax is the maximum concentration, Cτ is the concentration at the end of the interval between doses of the drug.

SPECIAL INSTRUCTIONS

Hypersensitivity reactions

Hypersensitivity reactions have been reported with the use of INIs, including Tivicay, and have been characterized by rash, impaired systemic parameters, and, occasionally, organ dysfunction, including liver damage.

If signs or symptoms of hypersensitivity occur (including, but not limited to, a severe rash or a rash accompanied by fever, general malaise, fatigue, muscle or joint pain.

Bullous lesions, lesions of the oral mucosa, conjunctivitis, facial edema, hepatitis, eosinophilia, angioedema) should immediately stop the use of the drug Tivicay and other drugs that could cause such reactions. It is necessary to monitor the clinical condition, including the parameters of hepatic aminotransferases, and conduct appropriate therapy.

Delay in discontinuing treatment with Tivicay* or other medicinal products that could cause similar reactions after hypersensitivity reactions have developed can lead to life-threatening reactions.

immune reconstitution syndrome

In HIV-infected patients with severe immunodeficiency, an inflammatory response to asymptomatic or residual opportunistic infections may occur at the time of initiation of APT, which may cause serious clinical conditions or exacerbation of symptoms. As a rule, such reactions were observed during the first few weeks or months after the start of APT. Typical examples of such conditions are cytomegalovirus retinitis, generalized and/or focal mycobacterial infections, and pneumonia caused by Pneumocystis jiroveci (P. carini). Any inflammatory symptoms should be assessed without delay and, if necessary, treatment initiated. Autoimmune diseases (such as Graves' disease, polymyositis, and Guillain-Barré syndrome) have been observed during immune reconstitution, but the time of onset varied and the disease could occur many months after initiation of therapy and have an atypical course. At the beginning of therapy with Tivicay, some patients with hepatitis B and or C coinfection experienced an increase in liver enzymes, reflecting the immune reconstitution syndrome. It is recommended to monitor liver enzyme activity in patients with hepatitis B and/or C coinfection. (see section "Side effects").

Opportunistic infections

Patients receiving Tivicay or another APT may develop opportunistic infections or other complications of HIV infection. Therefore, patients should be under close clinical supervision by a physician experienced in the treatment of HIV-related illnesses.

Transmission

Patients should be advised that there is no evidence to prevent the risk of sexually or bloodborne transmission of HIV to others when taking the currently available APT. including Tivicay. You must continue to take the necessary precautions.

Interaction with other drugs

Caution must be exercised when co-administered with medicinal products (prescription and non-prescription) that may alter exposure to dolutegravir or medicinal products whose exposure may be altered by dolutegravir (see section "Interaction with other drugsartificial preparations").

The recommended dose of Tivicay is 50 mg twice daily when co-administered with etravirine (not boosted by protease inhibitors), efavirenz, nevirapine, tipranavir/ritonavir. rifampicin, carbamazepine, phenytoin, phenobarbital and St. John's wort (see section interactions with other drugs).

Tivicay should not be co-administered with antacids containing variant cations. It is recommended to use Tivicay 2 hours before or 6 hours after the use of these drugs.

Tivicay is recommended to be taken 2 hours before or 6 hours after calcium or iron supplements, or alternatively taken with food (see section "Interaction with other drugs").

The drug Tivicay increases the concentration of mstformin. Dose adjustments of metformin should be considered at initiation and termination of co-administration of dolutegravir with metformin to maintain glycemic control. (see section "Interaction with other drugs").

Integrase inhibitor resistance of particular importance

When deciding on the use of dolutegravir in the presence of resistance to I&I, it should be taken into account that this significantly reduces the activity of dolutegravir against viral strains carrying secondary mutations Q148 + > 2 in the G140A/C/S, E138A/K/T, L74I regions. The extent to which dolutegravir provides additional efficacy in the presence of such INI resistance remains unclear.

osteonecrosis

Despite the fact that the etiology of this disease is multifactorial (including the use of corticosteroids, bisphosphonates, alcohol consumption, severe immunosuppression, high body mass index), cases of osteonecrosis most often occurred in patients with advanced HIV infection and/or long-term use of combined APT. Patients should see a doctor if they experience joint pain and stiffness or difficulty moving.

EFFECT ON ABILITY TO DRIVE VEHICLES AND MECHANISMS

No studies have been conducted on the effect of Tivicay on the ability to drive vehicles and operate machinery. The clinical condition of the patient and the adverse event profile of Tivicay should be taken into account when considering the patient's ability to drive or use machines.

RELEASE FORM

Film-coated tablets, 50 mg.
30 film-coated tablets in a high-density polyethylene vial with polyethylene heat-seal film and screw cap. 1 bottle with instructions for use in a cardboard box.

Best before date

2 years.
Do not use after the expiry date stated on the package.

STORAGE CONDITIONS

Store at a temperature not exceeding 30°C. Keep out of the reach of children.

HOLIDAY CONDITIONS

On prescription.

Manufacturer

"Glaxo Wellcome S.A."/Glaxo Wellcome S.A.
Avda. de Extremadura 3, 09400 Aranda de Duero. Burgos. Spain /
Avda. de Extremadura 3, 09400 Aranda de Ducro, Burgos, Spain

NAME AND ADDRESS OF THE LEGAL ENTITY IN WHICH NAME THE REGISTRATION CERTIFICATE IS ISSUED

ViiV Healthcare UK Limited / ViiV Healthcare UK Limited UK. TW8 9GS Middlesex. Brentford. Great West Road 980 / 980 Great West Road, Brentford, Middlesex TW8 9GS. United Kingdom

For more information please contact:

ZAO GlaxoSmntKline Trading
121614. Moscow, st. Krylatskaya, 17, bldg. 3. fl. 5
Business Park "Krylatsky Hills"