Tivikai - instructions for use, dose, side effects, contraindications

Active substanceDolutegravirDolutegravir

Similar drugsTo uncover

pills inwards

VeeV Helsker United Kingdom Limited United Kingdom

Dosage form: & nbspfilm-coated tablets

Composition:

Each tablet contains:

Component	Amount (mg)
Core tablet:
Active substance:
Dolutegravir sodium (in terms of dolutegravir)	52,6 (50,0)
Excipients:
Mannitol	145,4
Microcrystalline cellulose	60,0
Povidone-K29 / 32	15,0
Sodium carboxymethyl starch	21,0
Sodium fumarate	6,0
Tablet core weight	300,0
Film Sheath:
Fallen II yellow	9,0
Nominal tablet weight	309,0
Composition of Otradary II yellow:
Polyvinyl alcohol hydrolyzed	40,00
Titanium dioxide	23,45
Macrogol / polyethylene glycol	20,20
Talc	14,80
Dye iron oxide yellow	1,55

Description:

Round, biconvex tablets of yellow color. I with an engraved inscription "SV 572 "on one side and" 50 "on the other.

Pharmacotherapeutic group:antiviral [HIV] agent

ATX: & nbsp

J.05.A.X.12 Dolutegravir

Pharmacodynamics:

Dolutegravir inhibits HIV integrase by binding to the active region of integrase and blocking the chain transfer step during integration of retroviral deoxyribonucleic acid (DNA), which is necessary for the ECHI replication cycle. When carrying out the biochemical analysis of chain transfer using the purified integrals of HIV-1 and the pre-treated DNA substrate, IC₅₀ (concentration inhibiting replication by 50%) of 2.7 nM and 12.6 nM. In vitro dolutegravir dissociates slowly from the active center of the wild-type DNA integrase complex (T_{1/2 -}71 hours).

Pharmacodynamic effects

In a randomized study to determine the optimal dose for HIV-1 infected patients who received monotherapy with dolutegravir (ING11 1521), a rapid and dose-dependent antiviral effect was noted, with an average decrease in HIV-1 RNA for 11 days compared to the baseline level of 1.5, 2,0 and 2.5 log10 for 2 mg, 10 mg and 50 mg of dolutegravir for once-daily administration, respectively. This antiviral response was maintained for 3-4 days after the last dose was taken in the group of patients taking 50 mg of dolutegravir.

Antiviral activity in cell culture

In peripheral blood mononuclear cells (PBMCs) infected with a strain BaL HIV-1 or strain NL432 HIV-1, for dolutegravir were obtained IFROM₅₀ 0.51 nM and 0.53 nM, respectively. In MT-4 cells infected with the strain IIIIn HIV-1 and incubated with doltegravir for 4 or 5 days, IFROM₅₀ 0.71 and 2,1 NM.

In the analysis of the sensitivity of the viral integrase using the coding region of integrase from 13 clinically different isolatessubtype B, dolutegravir demonstrated antiviral activity similar to that of laboratory strains, with an average IC₅₀ 0.52 nM. In the analysis of the PBMC panel, consisting of 24 clinical isolates of HIV-1 [group M (subtypes A, B, C, D, B, F and G) and group O], as well as 3 clinical isolates of HIV-2, the geometric mean IC₅₀ was 0.20 nM, and the values IFROM₅₀ 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 the values IC₅₀ 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 assessments were performed in combination with stavudine, abacavir, efavirenz, nevirapine, lopinavir, amprenavir, enfuvirtide, maraviroc, adefovir and raltegravir, selected in checkerboard pattern). In addition, antiviral drugs without typical HIV activity (ribavirin) had no apparent effect on dolutegravir activity.

Influencedue Serum of blood and proteins of human serum

Research in vitro confirmed a 75-fold change (CI) IC₅₀ dolutegravir in the presence of 100% human blood serum (by extrapolation method), a IC₉₀, corrected for protein binding (PA-IC₉₀), in the IPPC was 64 ng / ml. The minimum concentration of doletegravir after a single dose of 50 mg in patients who had not previously taken integrase inhibitors (IIN) was 1.20 μg / ml, 19 times higher than the established PA-IC₉₀.

Sustainability in vitro

Isolates wild such as HIV-1: during the 112-day passage of the strain 1IIB there were no viruses with high resistance to doltegravir, the maximum 4.11-fold change was observed in groups of stable viruses with passages SI53Y and SI53F in the conservative positions of the integrase gene. Passage of the strain NL432 of the wild-type HIV-1 in the presence of dolutegravir led to the selection of substitution E92Q (the migrated group of the virus with CI = 3.1) and G193E (migraine group of virus with CI = 3.2) on day 56. Additional passage subtypes B, C and A/G wild type virus in the presence of dolutegravir led to breeding R263K, G118R and S153T.

Antiviral activity at resistant strains: strains, resistant to reverse transcriptase inhibitors (IOTs) and protease inhibitors (PIs): dolutegravir demonstrated the same activity against 2 non-nucleoside (HH) -IOT-resistant, 3 nucleoside (H) -IOT-resistant and 2 PI-resistant mutant clones of HIV-1 (1 with triple and 1 with sixfold resistance) in comparison with wild strain.

HIV-1 strains resistant to InI: 60 mutant HIV-1 isolates resistant to InI (28 with one substitution and 32 with 2 or more substitutions) were obtained from the wild type virus NL432 by site-directed mutagenesis. Dolutegravir demonstrated antiviral activity (sensitivity) against HIV with CI <5 to the ratio of 27 of 28 mutant viruses resistant to InI with one substitution, including T66A/I/K, E92Q/V, Y143C/H/R, Q148H/K/R and N155H, whereas for raltegravir and elvitegravir, activity was manifested in the ratio of 17/28 and 11/21 tested mutant viruses with CI <5, respectively. In addition, of the 32 mutant viruses resistant to InI with 2 or more replacements, 23 of 32 demonstrated CI <5 for dolutegravir compared with CI <5 for 4 of 32 for raltegravir and CI <5 for 2 of the 25 viruses tested for elvitegravir .

HIV-2 strains resistant to InI: viruses were obtained by site-directed mutagenesis of HIV-2 isolates isolated from HIV-2 infected patients who received raltegravir and in whom virological inefficiency of treatment was noted. In general, CI in HIV-2 was similar to HIV-1 CI, which was observed with a similar set of mutations. CI dolutegravir was <5 vs. 4 HIV-2 viruses (S163D, G140A/Q148R, A153G/N155H/S163G and E92Q/T97A/N155H/S163D); for E92Q/N155HC of dolutegravir was 8.5, and for G140S/Q148R CI Dolutegravir has left 17. Dolutegravir, raltegravir and elvitegravir showed the same activity against HIV-2 with a site-directed mutation with S163D, as for the wild type, and for the remaining mutant HIV-2 viruses, the RI ranges of raltegravir were 6.4-420, and the ranges of CI for elvitegravir were 22-640.

Clinical isolates in patients with virologic ineffectiveness of treatment with raltegravir: 30 clinical isolates with genotypic and phenotypic

resistance to raltegravir (median CI> 81) was examined for sensitivity to dolutegravir (median CI 1.5) by analysis with Monogram Biosciences PhenoSense. Mediene of CI dolutegravir for isolates with replacements in positions G140S + Q148H was 3.75; G140S + Q148R - 13.3; T97A + Y143R - 1.05 and N155H - 1.37.

705 resistant to raltegravir isolates obtained from patients who received raltegravir, were analyzed for sensitivity to doltegravir by analysis with Monogram Biosciences PhenoSense. Dolutegravir showed CI <10 in relation to 93.9% of 705 clinical isolates, while 16 (9%) of 184 isolates with replacement Q148+1 from resistance to InI and 25 (27%) of 92 clinical isolates with replacement 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 of resistance to InI or treatment-related resistance to nucleoside reverse transcriptase inhibitors (NRTIs) for treatment in previously untreated patients who took 50 mg of dolutegravir once a day (studies SPRING-1, SPRING-2, SINGLE and FLAMINGO). In the study SAILING in patients who received dolutegravir and previously not received InI (n= 354 in the dolutegravir group) associated with replacement therapy in integrase were observed at 48 weeks in 4 of 17 patients with virological inefficiency receiving dolutegravir. In 2 out of 4 patients, a unique replacement was observed R263K in the integrase gene with a maximum CI of 1.93, in 1 patient there was a polymorphic substitution V151V/I integrases with a maximum FC 0.92, and in 1 patient there were already initially integrase mutations and it is assumed that he had previously received InI or was infected with an InI resistant virus.

Sustainability in vivo: Patients with resistance to InI

In the study VIKING-3 studied dolutegravir (plus optimized baseline therapy) in patients with existing resistance to InI. Up to 24 weeks, 36 out of 183 patients reported a virological inefficiency (PDVF). Of these, 32 patients had paired baseline and PDVF-stability, and 17/32 (53%) showed mutations associated with treatment. The following treatment-related mutations or combinations of mutations have been observed: L74L/M (n=1), E92Q (n= 2), T97A (n= 9), E138K / A / T (n = 8), G140S (n= 2), Y143H (n= 1), S147G (n=1), Q148H /K/R (n = 4), N155H (n= 1) and E157E/Q (n= 1). In 14 of 17 patients with mutations of the virus associated with treatment, initially or in a history there was a mutation Q148. In 5 other patients, between weeks 24 and 48, PDVF, and y 2 Of these 5 patients, there were mutations that appeared during the treatment. The noted mutations that occurred during treatment, or combinations of mutations, were L74I (n=1), N155H (n=2).

In the study VIKING-4 studied dolutegravir (plus optimized base therapy) in 30 patients with primary genotypic resistance to InI detected during screening. The mutations that occurred during the treatment corresponded to the mutations observed in the study VIKING-3.

Influence on the parameters of the electrocardiogram (ECG)

In a randomized, cross-over, placebo-controlled clinical trial, 42 healthy volunteers received a single dose of placebo, a suspension of dolutegravir 250 mg (approximately 3 times the effect of a dose of 50 mg once a day in an equilibrium state) and moxifloxacin (400 mg, active control) order. Dolutegravir did not cause lengthening of the corrected interval (QTc) within 24 hours after taking the drug. After correction according to baseline ECG indices to placebo, the maximum mean change QTc, based on a correction by Frederick's formula (QTcF), was 1.99 msec (the upper limit of a 1-sided 95% confidence interval was 4.53 msec).

Effect on kidney function

The effect of dolutegravir on the serum creatinine clearance (CC), the glomerular filtration rate (GFR) in the sample with yogexol, and the effective renal plasma flux (EPP) in the sample with paraamine hippurate were evaluated in an open, randomized, placebo-controlled study in 3 groups with 37 healthy volunteers who received 50 mg dolutegravir 1 time per day (n= 12), 50 mg - 2 times a day (n= 13) or placebo 1 time per day (n= 12) within 14 days. There was a moderate decrease in QC when dolutegravir was administered during the first week of treatment, corresponding to a decrease that was observed in clinical studies. When taken in both doses dolutegravir had no significant effect on GFR or EPP. These data confirm studies in vitro, which suggest that small increases in creatinine levels observed in clinical studies are caused by non-pathological inhibition of the organic cation transfer agent 2 (OST2) in the proximal renal tubules, which causes tubular secretion of creatinine.

Pharmacokinetics:

The pharmacokinetics of dolutegravir in healthy volunteers and HIV-infected patients is the same. The variability of the pharmacokinetics of dolutegravir was low to moderate. In Phase 1 studies involving healthy volunteers, the coefficient of variation (CV) among participants for the area under the pharmacokinetic concentration-time curve (AUC) and for the maximum concentration (C_mOh) ranged from ~ 20 to 40%, and the concentration at the end of the dosing interval (C_τ) - from 30 to 65%. The variability of the pharmacokinetics of dolutegravir between participants was higher in HIV-infected patients than in healthy volunteers. Individual variability in pharmacokinetics was below the variability between inby the divisions.

Suction

Dolutegravir is rapidly absorbed after ingestion, the median time to the maximum concentration (T_mOh) after taking a dose in the form of tablets is 2-3 haca. The linearity of the pharmacokinetics of dolutegravir depends on the dose and dosage form. After oral administration dolutegravir in the form of tablets as a whole showed a nonlinear pharmacokinetics, with less than a dose-dependent increase in plasma exposure from 2 to 100 mg, but an increase in the exposure of dolutegravir is proportional to the dose from 25 mg to 50 mg.

Dolutegravir can be taken regardless of food intake. Food increases the degree and reduces the rate of absorption of dolutegravir. Bioavailability of dolutegravir depends on the food content: when eating with low, moderate and high fat content AUC_(0-∞) dolutegravir increased by 33%, 41% and 66%, C_mOh increased by 46%, 52% and 67%, T_mOh lengthened to 3, 4 and 5 hours compared to 2 hours when taken on an empty stomach, respectively. These increases are not clinically significant.

Absolute bioavailability of dolutegravir is not established.

Distribution

According to the data received in vitro, dolutegravir to a considerable extent (approximately 99.3%) binds to human plasma proteins. Apparent volume of distribution (after oral administration in the form of a suspension, Vd/F) is approximately 12.5 liters. The binding of dolutegravir to plasma proteins did not depend on concentration. The ratio of the total concentration of the radiolabeled drug in the blood and plasma was 0.441-0.535, indicating a minimal connection of the radiolabeled drug with the cellular components of the blood. The free fraction of dolutegravir in blood plasma is approximately 0.2-1.1% in healthy volunteers, approximately 0.4-0.5% in patients with moderate hepatic impairment, 0.8-1.0% in patients with renal failure severe insufficiency, and 0.5% in patients infected with HIV-1.

Dolutegravir penetrates into the cerebrospinal fluid (CSF). Twelve previously untreated patients who took dolutegravir and abacavir / lamivudine for 16 weeks, the mean concentration of dolutegravir in the CSF was 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 with an unbound concentration in the plasma). The ratio of concentration of doltegravir in CSF to the concentration in the blood plasma ranged from 0.11 to 2.04%. Concentrations of dolutegravir in CSF exceeded IC₅₀, which confirms a median decrease in the concentration of HIV-1 RNA in the CSF as compared to the initial concentration of 2.2 log after 2 weeks of therapy and 3.4 log after 16 weeks of therapy (see subsection "Pharmacodynamics").

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

Metabolism

Dolutegravir is mainly metabolized by uridine diphosphateglucoronosyltransferase UDF-GT1A1 with a minor isoenzyme component CYP3A (9.7% of the total dose taken in the study of mass balance in humans). Dolutegravir is the main compound circulating in the blood plasma, in unchanged form is slightly excreted through the kidneys (<1% dose).53% of the total dose taken orally is excreted unchanged through the intestine. It is not known whether this is due to incomplete absorption of the drug or excretion of the glucuronide conjugate with bile, which can further decay before the formation of related compounds in the lumen of the intestine. 31% of the total dose taken orally is excreted through the kidneys in the form of the glucuronide ester of dolutegravir (18.9% of the total dose), N-dialkylated metabolite (3.6% of the total dose) and a metabolite formed by oxidation of benzyl carbon (3.0% of the total dose).

Excretion

The final half-life of dolutegravir is about 14 hours, and the apparent clearance (CL/F) - 0.56 l / h.

Special patient groups

Children

In a pediatric study of 23 HIV-1-infected children and adolescents aged 12-18 years who received antiretroviral treatment earlier, the pharmacokinetics of dolutegravir in 10 children showed that a daily dose of 50 mg of dolutegravir led to the same exposure of dolutegravir in children and adolescents, as in adults, who received 50 mg of dolutegravir once a day.

Pharmacokinetic parameters in children (n=10)

Age / body weight

Dose dolutegravir

Evaluation of pharmacokinetic parameters of dolutegravir geometric mean (KB%)

AUC_(0-24)mcg^.h / ml

FROM_m_Ohmcg / ml

FROM₂₄mcg / ml

from 12 to <18 years, ≥ 40 kg^a

50 mg 1 time per day^a

46 (43)

3,49 (38)

0,90 (59)

^aone patient with a body weight of 37 kg received dolutegravir 35 mg once a day.

Elderly patients

Population pharmacokinetic analysis of dolutegravir using data obtained from adults infected with HIV-1 showed no clinically significant effect of age on the exposure of dolutegravir.

The pharmacokinetics of dolutegravir in patients over 65 years of age are limited.

Patients with impaired renal function

Renal clearance of the unchanged drug is a secondary way of deducing dolutegravir. A study was made of the pharmacokinetics of dolutegravir in patients with impaired renal function (TOK <30 ml / min). There were no clinically significant pharmacokinetic differences between patients with impaired renal function of severe degree (CK <30 mL / min) and healthy volunteers. Patients with impaired renal function are not required to adjust the dose. Dolutegravir It has not been studied in a group of patients on dialysis, however, differences in pharmacokinetics are not expected.

Patients with impaired hepatic function

Dolutegravir is metabolized and excreted mainly by the liver. In a study comparing 8 patients with moderate liver failure (class B on the Child-Pugh scale) and 8 healthy adult volunteers, the effect of a single dose of 50 mg dolutegravir was the same in the two groups. Patients with impaired liver function of mild or moderate severity do not need a dose adjustment. The effect of a severe liver dysfunction on the pharmacokinetics of dolutegravir has not been investigated.

Polymorphism of enzymes metabolizing drugs

There is no evidence that the frequent polymorphisms of drug-metabolizing enzymes change the pharmacokinetics of dolutegravir to a clinically significant extent. In a meta-analysis using pharmacogenomic samples obtained in clinical studies involving healthy volunteers in patients with genotypes of UDF-GT1A1 (n= 7), in which there was a weak metabolism of dolutegravir, the clearance of dolutegravir was reduced by 32%, a AUC was 46% higher than in patients with genotypes that were associated with normal metabolism via UDF-GT1A1 (n= 41). Isozyme polymorphism CYP3A4, CYP3A5 and NR112 was not associated with differences in the pharmacokinetics of dolutegravir.

Floor

Based on data obtained in a study involving healthy volunteers (men n= 17, women n= 24), it was found that the effect of dolutegravir is slightly higher in women (approximately 20%) than in men. Population pharmacokinetic analysis using aggregate pharmacokinetic data obtained in Phase IIb and Phase III clinical trials with the participation of adult patients, showed no clinically significant effect of sex on the exposure of dolutegravir.

Race

Populent pharmacokinetic analysis using the aggregate pharmacokinetic data obtained in clinical studies of the Phase IIb and Phases III with the participation of adult patients, showed no clinically significant effect of the race on the exposure of dolutegravir. It was proved that the pharmacokinetics of dolutegravir after single-entry intake by representatives of Japan is similar to the pharmacokinetics of Western nationalities (representatives of the United States).

Co-infection of HIV and viral hepatitis B or C

Population pharmacokinetic analysis showed that co-infection of the hepatitis C virus does not have a clinically significant effect on the effects of dolutegravir. Data on patients with co-infection with hepatitis B are limited.

Indications:Treatment of HIV-1 infections in adults and children from 12 years old and weighing 40 kg or more as part of combined antiretroviral therapy (Apt).

Contraindications:

- Hypersensitivity to dolutegravir or any other component included in the preparation;

- simultaneous reception with dofetilidom or pilsikainidom;

- Children under 12 years old and weighing less than 40 kg.

Carefully:

- Hepatic insufficiency of severe degree (class C on the Child-Pugh scale);

- with simultaneous use with medications (prescription and over-the-counter), which can alter the action of Tivicai®, or with drugs that may change under the action of Tivicay®.

Pregnancy and lactation:

Fertility

There are no data on the effect of Tivicay^® on the ability to conceive in men or women. Studies in animals showed a lack of influence of dolutegravir on the ability to conceive in males or females.

Pregnancy

Appropriate and well-controlled studies of Tivicay® with pregnant women have not been conducted. The effect of Tivicai® on pregnancy in women is unknown. In studies on reproductive toxicity in animals, it was shown that dolutegravir penetrates the placenta. Tivicay® can be used during pregnancy only if the expected benefit to the mother exceeds the potential risk to the fetus.

Breastfeeding period

HIV-infected patients are recommended not to breast-feed children to avoid vertical transmission of HIV infection.

Based on the data obtained from animals, it is expected that dolutegravir will be excreted in women with breast milk, although this has not been confirmed in humans.

Dosing and Administration:

Therapy with Tivicay® should be carried out by a doctor with experience in the treatment of HIV infection. Tivicay® can be taken without regard to food intake.

Adults

Patients infected with HIV-1, without resistance to InI

The recommended dose of Tivicai® is 50 mg once a day.

When used concomitantly with efavirenz, nevirapine, rifampicin, or tipranavir in combination with ritonavir, the recommended dose of Tivicay® in this category of patients should be 50 mg twice daily.

Patients infected with HIV-1, with resistance to InI (documented or suspected clinically)

The recommended dose of Tivicai® is 50 mg twice daily. The decision to use Tivicay® in such patients should be made taking into account the drug resistance to InI.

In this category of patients, simultaneous use with efavirenz, nevirapine, rifampicin or tipranavir in combination with ritonavir should be avoided.

Skipping the drug

If the patient misses Tivicay®, he should take the missed dose as soon as possible, if at least 4 hours remain before the next dose. If there is less than 4 hours left until the next dose, the patient should not take the missed dose, and the drug should be taken again according to the intake schedule.

Children aged 12 to 18 years and weighing 40 kg and more

The recommended dose of Tivicai® for patients who have not previously received InI treatment (age 12 to 18 years, body weight 40 kg and more) is 50 mg once a day.

There is insufficient data to recommend the dose of Tivicai® to children aged 12 to 18 years with resistance to InI.

Special patient groups

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

Insufficient safety and efficacy data are available for recommending a dose of Tivicaine® for children under 12 years of age or with a body weight of less than 40 kg.

Elderly patients

Data on the use of Tivicaine® in patients 65 years of age or older are limited. However, there is no data on the need for dose adjustment for elderly patients (see the section ("Pharmacokinetics"- "Special patient groups").

Patients with impaired renal function

Patients with impaired renal function of mild, moderate or severe severity (TOK <30 ml / min, not on dialysis) dose adjustment is not required. There is no data for of patients on dialysis, but no differences in pharmacokinetics in this population are expected (see section "Pharmacokinetics" - "Special patient groups").

Patients with impaired hepatic function

Patients with a mild or moderate severity of pensions (class A or B on the Child-Pugh scale) do not need a dose adjustment. There are no data on patients with severe hepatic dysfunction (class C by scale Child-Pugh) (see section "Pharmacokinetics" - "Special patient groups").

Side effects:

The undesirable reactions presented below are established during the analysis of the cumulative clinical trials data of Phases IIb and III, are listed in accordance with the system-organ classification and frequency of occurrence. Frequency of occurrence is defined as follows: Often (≥ 1/10), often (≥ 1/100 and <1/10), infrequently (≥ 1/1 000 and <1/100), rarely (≥ 1/10 000 and <1/1 000), rarely (<1/10 000, including individual cases).

Frequency of occurrence of undesirable reactions

Immune system disorders

Infrequent: hypersensitivity reaction, recovery syndrome immunity (see section "Special instructions").

Disorders of the psyche

Often: insomnia, unusual dreams, depression.

Infrequently: suicidal thinking or attempted suicide (especially in patients with a history of depression or mental illness).

Disturbances from the nervous system

Highly often: headache.

Often: dizziness.

Disorders from the gastrointestinal tract

Often: nausea, diarrhea.

Often: vomiting, flatulence, pain in the upper abdomen, pain in the area abdomen, discomfort in the abdomen.

Disturbances from the liver and bile ducts

Infrequently: hepatitis.

Disturbances from the skin and subcutaneous tissues

Often: rash, itching.

General disorders and disorders at the site of administration

Often: fatigue.

Laboratory and instrumental data

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

The safety profile was the same in populations of patients who had not previously received treatment, patients treated (except for InI), and patients with resistance to InI.

Changes in laboratory indicators

During the first week of treatment with Tivicai®, there was an increase in the serum creatinine concentration, which persisted for 48 weeks. In the treatment of patients who had not previously received therapy, the average change was 9, 96% μmol / L compared to the initial concentration (range: -53 μmol / L to 54.8 μmol / L) observed after 48 weeks of treatment.The increase in creatinine concentration was comparable to the concentration observed with the use of basic NRTIs, and did not differ from the concentration that was observed in patients previously treated. This change is not considered clinically significant because it does not reflect changes in glomerular filtration rate (see the section "Pharmacodynamics" - "Influence on kidney function").

In the program to study the drug in the groups of dolutegravir and raltegravir (but not efavirenz), there were insignificant increases in the concentration of total bilirubin (without clinical jaundice). These changes are not considered clinically significant, as they probably reflect the competitive clearance of dolutegravir and unconjugated bilirubin through UDF-GT1A1 (see section "Pharmacokinetics" - "Metabolism").

Also during the therapy with dolutegravir, asymptomatic increases in the activity of CK were registered, which were mainly associated with physical activity.

Use in children

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

Co-infection of HIV and hepatitis B or C

Phase III studies were allowed to include patients with co-infection with hepatitis B and / or C, provided that the results of the initial laboratory parameters of liver function did not exceed the upper limit of the norm (VGN) by 5 times. In general, the safety profile in patients with co-infections of hepatitis B and / or C was the same as in patients without co-infection with hepatitis B or C, despite the fact that the frequency of the concentration deviations ACT and ALT was higher in a subgroup of patients with co-infections of hepatitis B and / or C in all treatment groups. An increase in hepatic enzyme activity corresponding to the immune reconstitution syndrome was observed in several patients with co-infection of hepatitis B and / or C at the beginning of therapy with Tivicai®, especially in those who had hepatitis B (see section "Special instructions").

Post-registration data

No data available.

Overdose:

Symptoms

Data on the overdose of Tivicaine® are limited. The limited experience of using higher single doses (up to 250 mg in healthy volunteers) revealed no special symptoms or signs other than those described in the "Side effect" section.

Treatment

Further treatment should be carried out in accordance with clinical indications or recommendations of the National Toxicology Center, where applicable. There is no specific treatment for overdose with Tivicay®. In case of an overdose, supportive therapy and appropriate follow-up should be performed. Due to the high binding of dolutegravir to plasma proteins, it is unlikely that a significant amount of it can be eliminated by dialysis.

Interaction:

Effect of dolutegravir on the pharmacokinetics of other drugs

h vitro dolutegravir demonstrates no direct inhibition or weak inhibition (IC₅₀> 50 μM) of cytochrome P system isoenzymes₄₅₀ (CYP)1A2. CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 CYP3A, УДФ-ГТ1А1 or УДФ-ГТ2В7, or vectors Pgp, BCRP, BSEP, OATP1B1, OATP1B3, OST1, MRP2 or MRP4. In vitro dolutegravir does not induce isoenzymes CYP1A2, CYP2B6 or CYP3A4. In vivo dolutegravir has no effect on midazolam, activity indicator CYP3A4. Based on these data, it is not expected that the drug Tivicay^® can affect the pharmacokinetics of drugs that are substrates of these enzymes or vectors (for example,reverse transcriptase or protease inhibitors, abacavir, zidovudine, maraviroc, opioid analgesics, antidepressants, statins, azole fungicides, proton pump inhibitors, drugs for the treatment of erectile dysfunction, acyclovir, valaciclovir, sitagliptin, adefovir).

In studies of drug interactions dolutegravir did not have a clinically significant effect on the pharmacokinetics of the following drugs: tenofovir, ritonavir, methadone, efavirenz, lopinavir, atazanavir, darunavir, etravirine. fosamprenavir, rilpivirine, boceprevir, telaprevir, daklataswir and oral contraceptives containing norgestimate and ethinyl estradiol.

In vitro dolutegravir inhibited the renal transporter of organic cations 2 (OCT2) (IC₅₀ ⁼ 1.93 μM), excretory vector of various drugs and toxins (MATE) 1 (IC₅₀ = 6.34 μM) and MATE2-K (IC₅₀ = 24.8 μM). Taking into account the exposition dolutegravir in vivo, Potential impact on transport of substrates is unlikely 1VATE2-K in vivo. In vivo dolutegravir can increase the concentration of drugs in blood plasma, the removal of which depends on OST2 or MATE1 (dofetilide, pilsikainid or metformin) (see table 1).

In vitro dolutegravir inhibited basolateral carriers in the kidney: a carrier of organic anions (OAT) 1 (IC₅₀ = 2.12 μM) and OAT3 (IC₅₀ = 1.97 μM). but dolutegravir did not have a pronounced effect on the pharmacokinetics in vivo substrates OAT of tenofovir and para-aminoghippurate, and thus had a weak ability to induce drug interactions by inhibiting the carriers ABOUTAT.

Influence of other means on pharmacokinetics of doltegravir

Dolutegravir is excreted mainly by the metabolism of UDF-GT1A1. Dolutegravir is also a substrate of UDF-GT1A3, UDF-GT1A9, CYP3A4, Pgp and BCRP; therefore, drugs that induce these enzymes or vectors can theoretically reduce the concentration of dolutegravir in the blood plasma and reduce the therapeutic effect of Tivicai®

The simultaneous use of Tivicai® and other drugs that inhibit UDF-GT1A1, UDF-GT1A3, UDF-GT1A9, CYP3A4 and / or Pgp. can increase the concentration of dolutegravir in the blood plasma (see Table 1).

In vitro dolutegravir is not a substrate of the human transport polypeptide of organic anions (OATP) lBl, OATP1B3 or OST1, therefore it is not expected that preparations modulating exclusively the activity of these vectors will affect the concentration of dolutegravir in blood plasma.

Efavirenz, etravirine, nevirapine, rifampicin, carbamazepine and tipranavir in combination with ritonavir significantly reduced the concentration of dolutegravir in blood plasma and therefore, correction of the dose of Tivicai® to 50 mg twice a day is necessary. The effect of etravirine was weakened by the simultaneous use of inhibitors CYP3A4 lopinavir / ritonavir, darunavir / ritonavir, and is expected to be weakened by atazanavir / ritonavir. Thus, with the simultaneous use of dolutegravir with etravirine and either lopinavir / ritonavir, darunavir / ritonavir, or atazanavir / ritonavir, dose adjustment of Tivicay® is not required.

Another inductor, fosamprenavir, in combination with ritonavir. reduced the concentration of dolutegravir in blood plasma, but dose adjustment of Tivicaine® is not required (see Table 1). The study of interaction with the inhibitor UDF-GT1A1, atazanavir, did not show a clinically significant increase in dolutegravir concentrations in blood plasma. Tenofovir, lopinavir / ritonavir, darunavir / ritonavir, rilpivirine, boceprevir, telaprevir, prednisone, rifabutin, daklataswir and omeprazole did not have any effect or had a minimal effect on the pharmacokinetics of dolutegravir, therefore, with simultaneous use with these medications, dosage adjustment of the Tivicaine® preparation is not required.

Interactions with individual drugs are presented in Table 1. Recommendations are based either on studies of interaction with other drugs or on predictable interactions due to the expected amplitude of interactions and the likelihood of developing serious adverse events or loss of efficacy.

Table 1. Interaction with other drugs

Class concomitant medicinal preparation: name medicinal preparation	Influence at concentration dolutegravir either concomitant medicinal preparation	Comments
Antiviral drugs drugs for HIV-1 treatment
Non-nucleoside inhibitor reverse transcriptase: etravirine without intensify inhibitors proteases	Dolutegravir ↓ AUC↓ 71% FROM_m_Oh ↓52% St ↓ 88% etravirine ↔	Etravirine, without amplification by protease inhibitors, reduces the concentration of dolutegravir in blood plasma. The recommended dose of dolutegravir is 50 mg 2 once daily for simultaneous use with etravirine without enhancing protease inhibitors. Do not take Tivicay® with etravirine without simultaneous use of atazanavir / ritonavir, darunavir / ritonavir or lopinavir / ritonavir in patients with resistance to InI.
Protease inhibitor: lopinavir / ritonavir + etravirine	Dolutegravir ↔ AUC ↑ 11% FROM_m_Oh ↑ 7% Сτ ↑ 28% lopinavir ↔ ritonavir ↔	Lopinavir / ritonavir and etravirine Do not change the concentration of dolutegravir in blood plasma in a clinically significant degree. No dose adjustment is required.
Protease inhibitor: darunavir / ritonavir + etravirine	Dolutegravir ↓ AUC ↓ 25% FROM_m_Oh ↓ 12% St ↓ 36% darunavir ↔ ritonavir ↔	Darunavir / ritonavir and etravirine Do not change the concentration of dolutegravir in blood plasma in a clinically significant degree. No dose adjustment is required.
Non-nucleoside reverse transcriptase inhibitor: efavirenz	Dolutegravir ↓ AUC ↓ 57% FROM_m_Oh ↓ 39 % St ↓ 75% efavirenz ↔	Efavirenz reduces the concentration of dolutegravir in blood plasma.With simultaneous use with efavirenz, the recommended dose of Tivicaine® is 50 mg 2 times a day. If possible, patients with resistance to InI should use alternative combinations that do not include efavirenz.
Non-nucleoside inhibitor reverse transcriptase: nevirapine	Dolutegravir ↓	Simultaneous use with nevirapine has not been studied and may lead to a decrease in plasma doltegravir concentration due to induction of the enzyme. The effect of nevirapine on dolutegravir exposure is probably the same or less than the effect of efavirenz. With simultaneous use with nevirapine, the recommended dose of Tivicaine® is 50 mg 2 times a day. If possible, alternative combinations should be used that do not include nevirapine, patients with resistance to InI.
Protease inhibitor: atazanavir	Dolutegravir ↑ AUC ↑ 91% FROM_m_Oh ↑ 50% St ↑ 180% Atazanavir ↔	Atazanavir increases the concentration of dolutegravir in the blood plasma. No dose adjustment is required.
Protease inhibitor: atazanavir / ritonaviR	Dolutegravir ↑ AUC ↑ 62% FROM_m_Oh ↑ 34% St ↑ 121% atazanavir ↔ ritonavir ↔	Atazanavir / ritonavir increased the concentration of dolutegravir in the blood plasma. No dose adjustment is required.
Rilpivirine	Dolutegravir ↔ AUC ↑ 12% C_max↑ 13% St ↑ 22% rilpivirin ↔	No dose adjustment is required.
Protease inhibitor: tipranavir / ritonavir	Dolutegravir ↓ AUC ↓ 59% C_max ↓ 47% St ↓ 76% tipranavir ↔ ritonavir ↔	Tipranavir / ritonavir reduces concentrations of dolutegravir. When used simultaneously with tipranavir / ritonavir, the recommended dose of Tivicaine® is 50 mg twice daily. If possible, patients with resistance to InI should use alternative combinations that do not include tipranavir / ritonavir.
Protease inhibitor: fosamprenavir / ritonavir	Dolutegravir ↓ AUC ↓ 35% C_max ↓24% St ↓ 49% Fosamprenavir ↔ Ritonavir ↔	Fosamprenavir / ritonavir decreases the concentrations of dolutegravir, but, based on limited data, did not lead to a decrease in the efficacy of dolutegravir in Phase III studies. There is no need for dose adjustment for patients who have not previously received InI. If possible, alternative combinations that do not include fosamprenavir / ritonavir should be used, in patients with resistance to InI.
Protease inhibitor: nelfinavir	Dolutegravir ↔	This interaction was not investigated. Despite the fact that it is an inhibitor of CYP3A4, based on data obtained for other inhibitors, no increase is expected. No dose adjustment is required.
Protease inhibitor: lopinavir / ritonavir	Dolutegravir ↔ AUC ↓ 4% FROM_m_Oh ↔ St ↓ 6% lopinavir ↔ ritonavir ↔	Lopinavir / ritonavir did not change the concentration of dolutegravir in blood plasma to a clinically significant extent. No dose adjustment is required.
Protease inhibitor: darunavir / ritonavir	Dolutegravir ↓ AUC ↓ 22% FROM_m_Oh ↓ 11% St ↓ 38%	Darunavir / ritonavir did not change the concentration of dolutegravir in blood plasma to a clinically significant extent. No dose adjustment is required.
Han ukleoside reverse transcriptase inhibitor: tenofovir	Dolutegravir ↔ AUC ↔ FROM_max ↓ 3% Сτ ↓ 8% tenofovir ↔ AUC ↑ 12% FROM_m_Oh ↑ 9% St ↑ 19%	Tenofovir is not changed the concentration of dolutegravir in blood plasma in a clinically significant degree. no dose adjustment is required.
other means
dofetilide pilsicainide	dofetilide ↑ pilsicainide ↑	simultaneous use with doltegravir can increase the concentration of dofetilide or pilsicainide in blood plasma by inhibiting the carrier ost2; simultaneous application was not investigated. the simultaneous use of dofetilide or pilsicainide with dolutegravir is contraindicated because of the possible life-threatening toxicity caused by a high concentration of dofetilide or pilsicainide.
carbamazepine	dolutegravir ↓ auc ↓ 49% c_max ↓ 33% сτ ↓ 73%	Carbamazepine will reduce the concentration of dolutegravir in the blood plasma. the recommended dose of dolutegravir is 50 mg 2 times a day when combined with carbamazepine. If possible, patients with resistance to inulin should use alternative drugs instead of carbamazepine.
phenytoin phenobarbital preparations of St. John's wort perforated	dolutegravir ↓	the simultaneous use of metabolism with these inducers has not been studied and, probably, reduces the concentration of dolutegravir in blood plasma due to the induction of the enzyme. The effect of these metabolism inducers on the exposure of dolutegravir appears to be similar to that of carbamazepine. the recommended dose of the drug tivikai® is 50 mg 2 times a day when applied with these metabolism inducers. if possible, patients with resistance to ini should use alternative combinations that do not include these metabolism inducers.
oxcarbazepine	dolutegravir ↓	this interaction has not been studied. despite the fact that the drug is an inducer of cyp3a4, based on the data obtained for other inducers, a clinically significant decrease in dolutegravir is not expected.no dose adjustment is required.
azole antifungal drugs ketoconazole fluconazole itraconazole Plucoprazole voriconazole	dolutegravir ↔ (not studied)	no dose adjustment is required. on the basis of data obtained with the use of other inhibitors of cyp3a4, a marked increase in concentration is not expected.
antacids containing polyvalent cations (e.g., mg, al)	dolutegravir↓ auc ↓ 74% c_max ↓ 72% from₂₄ ↓ 74%	simultaneous use of antacids containing polyvalent cations, can reduce the concentration of dolutegravir in the blood plasma. It is recommended to use the drug tivikai® for 2 hours before or after 6 hours after the use of antacid preparations containing polyvalent cations.
calcium preparations	dolutegravir ↓ auc ↓ 39% from_max ↓ 37% from₂₄ ↓ 39%	preparation of Tivicay® is recommended for 2 hours before or after 6 hours after taking medications that contain calcium. when taking with food, the drug tivikai® can be taken concomitantly with calcium preparations.
iron preparations	dolutegravir ↓ auc ↓ 54 % from_max ↓ 57 % from₂₄ ↓ 56 %	preparation of Tivicay® is recommended for 2 hours before or after 6 hours after taking medications containing iron.when taking with food, the drug tivikai® can be taken concomitantly with iron preparations.
multivitaminsnnth drug	dolutegravir ↓ auc ↓ 33 % from_max↓ 35% from₂₄ ↓ 32% (complex binding to polyvalent ions)	preparation of Tivicay® is recommended for 2 hours before or after 6 hours after taking multivitamin preparations.
corticosteroids prednisone	dolutegravir ↔ auc ↑ 11% from_m_Oh ↑ % ct ↑ 17%	no dose adjustment is required.
metformin	metformin ↑ when used together with dolutegravir 50 mg 1 times / day: metformin auc ↑ 79% from_m_Oh ↑ 66% when used together with dolutegravir 50 mg 2 times / day: metformin auc ↑ 145% from_m_Oh ↑ 111%	simultaneous use of the drug tivicai® can increase concentrations of metformin in the blood plasma. Mr.It is necessary to consider the possibility of dose adjustment metformin at the beginning and at the termination of the joint application of dolutegravir with metformin, to maintain glycemic control.
rifampicin	dolutegravir ↓ auc ↓ 54% from_m_Oh ↓ 43% ct ↓ 72%	rifampicin reduces the concentration of dolutegravir in the blood plasma. when used with rifampicin, the recommended dose of tivicai® is 50 mg twice a day.If possible, patients with resistance to PAlternate rifampicin drugs.
rifabutin	dolutegravir ↔ auc ↓ 5% from_m_Oh ↑ 16% ct ↓ 30% (induction of enzymes udf-rmal and cyp3a)	no dose adjustment is required.
oral contraceptives (ethinyl estradiol and norgestromine)	effect of doltegravir: ethinyl estradiol ↔ auc ↑ 3% from_m_Oh ↓ 1% ct ↑ 2% doltegravir effect: norgestromine ↔ auc ↓ 2% from_m_Oh ↓ 11% ct ↓ 7%	dolutegravir does not change the concentration of ethinylestradiol and norgestromine in the blood plasma to a clinically significant extent. It is not necessary to correct the dose of oral contraceptives when used simultaneously with the drug tivikai®.
methadone	doltegravir effect: methadone ↔ auc ↓ 2% from_m_Oh ↔ 0% ct ↓ 1%	dolutegravir does not change the concentration of methadone in the blood plasma to a clinically significant extent. It is not necessary to correct the dose of methadone when used simultaneously with the drug tivikai®.
telaprevir	dolutegravir ↑ auc ↑ 25 % from_m_Oh ↑19% ct ↑ 37% telaprevir ↔ (historical control) (inhibition enzyme cyp3a)	no dose adjustment is required.
boceprevir	dolutegravir ↔ auc ↑ 7% c_max ↑ 5% ct ↑ 8%	no dose adjustment is required.
daklataswir	dolutegravir ↔ auc ↑ 33% from_m_Oh ↑ 29% ct ↑ 45% daklataswir	daklatasvir does not change the concentration of dolutegravir in plasma in a clinically significant degree. dolutegravir does not change the concentration of daklatasvir in blood plasma. no dose adjustment is required.

reduction: ↑ - increase; ↓- reduction; ↔ - no significant changes; auc - the area under the concentration-time curve, c_max-maximum concentration, s_τ- concentration at the end of the interval between doses of the drug.

Special instructions:

Hypersensitivity reactions

When using InI, including Tivikai®, hypersensitivity reactions were recorded that were characterized by a rash, a violation of systemic indices and, sometimes, a violation of organ function, including liver damage. If there are signs or symptoms of hypersensitivity (including but not limited to a severe rash or rash accompanied by fever, general malaise, fatigue, muscle or joint pain, bullous lesions, mucous membrane damage to the oral cavity, conjunctivitis, facial edema, hepatitis , eosinophilia,angioneurotic edema), it is necessary to immediately discontinue the use of Tivicay^® and other medications that could cause similar reactions. It is necessary to monitor the clinical state, including the parameters of hepatic aminotransferases and conduct appropriate therapy. The delay in stopping treatment with Tivicay® or other medications that could trigger such reactions, after the development of hypersensitivity reactions, can lead to life-threatening reactions.

Immunodeficiency Syndrome

In HIV-infected patients with severe immunodeficiency during the onset Apt There may be an inflammatory response to asymptomatic or residual opportunistic infections that can cause serious clinical conditions or worsen symptoms. As a rule, such reactions were observed during the first few weeks or months after the onset Apt. Typical examples of such conditions are cytomegalovirus retinitis, generalized and / or focal mycobacterial infections and pneumonia caused by Pneumocystis jiroveci (R. carinii). It is necessary to immediately evaluate any inflammatory symptoms and, if necessary, begin treatment. Autoimmune diseases (such as Graves' disease, polymyositis and Guillain-Barre syndrome) were observed against the background of restoration of immunity, but the time of primary manifestations varied, and the disease could occur many months after the initiation of therapy and have an atypical course.

At the beginning of therapy with Tivicay®, in some patients with co-infection with hepatitis B and / or C, an increase in the activity of liver enzymes, reflecting the immune reconstitution syndrome, was observed. It is recommended to monitor the activity of liver enzymes in patients with co-infection with hepatitis B and / or C. Special control is needed for the initiation or continuation of hepatitis B therapy (according to the current guidelines) in patients who are treated with dolutegravir (see section "Side effect").

Opportunistic infections

In patients receiving Tivicai® or another drug Apt, opportunistic infections or other complications of HIV infection may develop. Therefore, patients should be under close clinical supervision of a physician with experience treatment of HIV-related diseases.

Transmission of infection

Patients should be informed that the prevention of the risk of transmission of HIV to others by sexual transmission or through the blood has not been proven with the availability of an affordable at present time Apt, including the drug Tivikai^®. It is necessary to continue to take the necessary precautions.

Interaction with other drugs

Care must be taken when using drugs (prescription and over-the-counter) that can change the exposure of dolutegravir, or with drugs that can be exposed under the action of dolutegravir (cm. section "Interaction with other medicinal products").

The recommended dose of Tivicay® is 50 mg twice daily for simultaneous use with etravirine (without potentiation by protease inhibitors), efavirenz, nevirapine, tipranavir / ritonavir, rifampicin, carbamazepine, phenytoin, phenobarbital and St. John's wort (see the section "Interaction with other medicinal products").

The drug Tivicai® should not be administered together with antacids containing polyvalent cations. It is recommended that Tivicay® is used 2 hours before or 6 hours after the application of these drugs (see the section "Interaction with other medicinal products").

Preparation Tivicai® is recommended to be taken 2 hours before or 6 hours after taking calcium-containing or iron-containing food supplements or, alternatively, taken with food (see section "Interaction with other medicinal products").

A drug Tivicai® raises concentrations of metformin. It is necessary to consider the possibility of correcting the dose of metformin at the beginning and at the termination of the joint application of dolutegravir with metformin. to maintain glycemic control (see section "Interaction with other medicinal products").

Resistance to integrase inhibitors of special significance

When deciding on the use of dolutegravir in the presence of resistance to InI, it should be borne in mind that the activity of dolutegravir significantly decreases with respect to viral strains bearing secondary mutations Q148+> 2 in sections G140A/C/S, Е138А / К / Т, L74I. Degree in which dolutegravir provides dAdditional efficacy in the presence of such resistance to InI remains unclear.

Osteonecrosis

Despite the fact that the etiology of this disease is multifactorial (including the use of corticosteroids, diphosphonates, alcohol consumption, severe immunosuppression, high body mass index), cases of osteonecrosis were most often encountered in patients at a late stage of HIV infection and / or long-term combined Apt. Patients should consult a doctor if they experience pain and stiffness in the joints or difficulty moving.

Effect on the ability to drive transp. cf. and fur:

Studies of the effect of Tivicai® on the ability to drive vehicles and work with mechanisms have not been conducted. It is necessary to take into account the clinical condition of the patient and the profile of undesirable phenomena of Tivicay^® when considering the patient's ability to drive or operate machinery.

Form release / dosage:

Tablets, film-coated, 50 mg.

Packaging:

For 30 tablets, film-coated, in a vial of high-density polyethylene,equipped with a polyethylene thermo-sealing film and a screw cap.

1 bottle with instructions for use in a cardboard pack.

Storage conditions:

Store at a temperature not exceeding 30 ° C.

Keep out of the reach of children.

Shelf life:

2 years.

Do not use after the expiration date stated on the package.

Terms of leave from pharmacies:On prescription

Registration number:LP-002536

Date of registration:16.07.2014

Date of cancellation:2019-07-16

The owner of the registration certificate:VeeV Helsker United Kingdom LimitedVeeV Helsker United Kingdom Limited United Kingdom

Manufacturer: & nbsp

GLAXO WELLCOME, S.A. Spain

GLAXO OPERATIONS UK, Limited United Kingdom

Representation: & nbspGlaxoSmithKline Trading, ZAOGlaxoSmithKline Trading, ZAO

Information update date: & nbsp18.01.2016

Illustrated instructions

Instructions

Tivicay® (Tivicay®)