Composition, form of production and packaging
The tablets covered with a film cover of yellow color, round, biconcave, engraved with the inscription "SV 572" on one side and "50" on the other side.
1 tab.
dolutegravir sodium 52.6 mg
which corresponds to the content of dolutegravir 50 mg
[PRING] mannitol 145.4 mg, microcrystalline cellulose 60 mg, povidone-K29 / 32 15 mg, sodium carboxymethyl starch 21 mg, sodium stearyl fumarate 6 mg.
Composition of the film coat: Opadrai II yellow 9 mg, including polyvinyl alcohol hydrolyzed 40%, titanium dioxide 23.45%, macrogol 20.2%, talc 14.8%, iron dye oxide yellow 1.55%.
30 pcs. - polyethylene bottles (1) - cardboard packs.
INSTRUCTION FOR THE SPECIALIST.
Description of the drug approved by the manufacturer for the printed edition of 2014.
PHARMACHOLOGIC EFFECT
Mechanism of action
Dolutegravir inhibits HIV integration by binding to the active region of integrase and blocking the chain transfer during integration of retroviral deoxyribonucleic acid (DNA), which is necessary for the HIV replication cycle. In vitro, dolutegravir is slowly separated from the active site of the wild-type DNA integrase complex (T 1/2 71 h).
Pharmacodynamic effects
In a randomized study to determine the optimal dose for HIV-1 infected patients who received dolutegravir monotherapy, a rapid and dose-dependent antiviral effect was noted. The mean reductions in HIV-1 RNA for 11 days compared to baseline were 1.5, 2.0 and 2.5 log10 for 2 mg, 10 mg, and 50 mg of dolutegravir once daily, 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 (PBMC) infected with the HIV-1 strain BaL or the HIV-1 strain NL432, for dolutegravir, IC50 (a concentration that inhibits replication by 50%) was 0.51 nM and 0.53 nM, respectively. In the MT-4 cells infected with HIV-1 strain IIIB and incubated with doltegravir for 4 or 5 days, an IC50 of 0.71 and 2.1 nM was obtained. In two biochemical tests in vitro to transfer DNA chains using purified HIV-1 integrase and a pre-treated DNA substrate, an IC50 of 2.7 nM and 12.6 nM was obtained.
In the sensitivity analysis of viral integrase using the integrase coding region of 13 clinically different subtype B isolates, dolutegravir demonstrated antiviral activity similar to that of laboratory strains with an average IC50 of 0.52 nM. In the analysis on the PBMC panel consisting of 24 clinical isolates of HIV-1 [group M (subtypes A, B, C, D, E, F and G) and group O], as well as 3 clinical isolates of HIV-2, 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 1C50 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 exhibited antagonism to dolutegravir (in vitro, the evaluation was performed in combination with stavudine, abacavir, efavirenzem, nevirapine, lopinavir, amprenavir, enfuvirtide, maraviroc, adefovir and raltegravir, selected in staggered order) . In addition, antiviral drugs with no typical HIV activity (ribavirin) did not have a visible effect on dolutegravir activity.
Effect on serum and human serum proteins
In vitro studies confirmed a 75-fold change in the (CI) 1C50 dolutegravir in the presence of 100% human serum (by extrapolation), and IC90, corrected for protein binding (PA-IC90), in the PBMC was 64 ng / ml. The steady concentration of dolutegravir after a single dose of 50 mg in patients who had not previously taken integrase inhibitors (INI) was 1.20 Ојg / ml and thus was 19 times higher than the established PA-IC90.
In vitro resistance
Wild-type isolates of HIV-1: during the 112-day passage of strain IIIB viruses with high resistance to doltegravir were not detected, the maximum 4.1-fold change was observed in groups of stable viruses with passages that replaced S153Y and S153F in conservative positions of the integrase gene. The passage of the wild-type strain NL-432 of HIV-1 in the presence of dolutegravir resulted in the selection of the replacement E92Q (the migrated group of the virus with CI = 3.1) and G193E (the resected group of the virus with CI = 3.2) on day 56. An additional passage of subtypes B, C and A / G of wild-type virus in the presence of dolutegravir led to the selection of R263K, G118R and S153T.
Antiviral activity against resistant strains: strains resistant to reverse transcriptase inhibitors (PIs) and protease inhibitors (DPI): dolutegravir demonstrated the same activity against 2 non-nucleoside (HH) -IOT-resistant, 3 nucleoside (H) -IOT-resistant and 2 IP-resistant mutant clones of HIV-1 (1 with triple and 1 with sixfold resistance) in comparison with wild strain.
HIV-1 strains resistant to integrase inhibitors: 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 directed mutagenesis. Dolutegravir demonstrated antiviral activity (sensitivity) against HIV with CI <5 for 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, while for raltegravir and elvitegravir it manifested itself in the ratio of 17/28 and 11/21 tested mutant viruses with CI <5, respectively. In addition, out of 32 mutant viruses resistant to integrase inhibitors with 2 or more substitutions, 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 elvitegravir.
HIV-2 strains resistant to InI: viruses were obtained by directed mutagenesis of HIV-2 isolates isolated from infected HIV-2 patients who received raltegravir and who had a viral ineffectiveness of treatment. 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 D92Q / N155H, KI dolutegravir was 8.5, and for G140S / Q148R, the CI of dolutegravir was 17. Dolutegravir, raltegravir, and elvitegravir showed the same activity against HIV-2 with a directed mutation with S163D as in the wild type, and for the remaining mutant viruses HIV-2 ranges of CI raltegravir were 6.4-20, and the ranges of CI for elvitegravir were 22-640.
Clinical isolates in patients with virological ineffectiveness of raltegravir: 30 clinical isolates with genotypic and phenotypic resistance to raltegravir (median CI> 81) were examined for sensitivity to doltegravir (median CI 1.5) by analysis with Monogram Biosciences PhenoSense. The median CI of dolutegravir for isolates with replacements in positions G140S + Q148H was 3.75; G140S + Q148R-13.3; T97A + Y143R - 1.05 and N155H - 1.37. The 705 raltegravir-resistant isolates obtained from patients treated with raltegravir were analyzed for sensitivity to doltegravir by analysis with Monogram Biosciences PhenoSense. Dolutegravir showed CI <10 for 93.9% of 705 clinical isolates.
In vivo resistance: patients who did not take InI
There was no evidence of mutations in resistance to InI or treatment-related resistance to nucleoside reverse transcriptase inhibitors (NRTIs) of primary therapy in previously untreated patients who took 50 mg of Tivicai drug once a day (SPRING-1, SPRPNG-2 and SINGLE) . In the SAILING study, patients treated with Tivicai and previously uninfected with InI (n = 354 in the dolutegravir group), treatment-related resistance to InI was observed at 48 weeks in 4 of 17 patients with virological inefficiency receiving dolutegravir. In 2 of 4 patients, a unique replacement of R263K in the integrase gene with a maximal CI of 1.93 was observed, in 1 patient there was polymorphic replacement of V151V / I integrase with a maximum FC of 0.92, and in 1 patient there were already initially integrase mutations and, he previously received an InI or was infected with a resistant to InI virus.
In vivo resistance: patients with resistance to InI
In the VIKING-3 study, the Tivicay preparation (plus optimized basal therapy) was studied in patients with existing resistance to InI. Up to 24 weeks, 36 out of 183 patients reported a protocol-established virological inefficiency (PDVF). Of these, 31 patients had paired data for baseline and PDVF resistance for analysis and 16/31 (52%) had treatment-related mutations. The following treatment-related mutations or combinations of mutations were observed: L74L / M (n = 1), E92Q (n = 2), T97A (n = 8), E138K / A (n = 7), 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 16 patients with mutations of the virus associated with treatment, initially or in an anamnesis there was a mutation Q148.
Influence on ECG parameters
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 prolongation of the QT interval within 24 hours after taking the drug. After correction for ECG baseline and placebo, the maximum mean QT change based on the Fridericia (QTcF) correction was 1.99 ms (the upper limit of the 1-way 95% confidence interval was 4.53 ms).
Effect on kidney function
The effect of the Tivicay preparation 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 para-aminoghippurate were evaluated in an open, randomized, placebo-controlled study in 3 groups with 37 healthy volunteers, who took 50 mg of Tivikai drug once a day (n = 12), 50 mg twice a day (n = 13) or placebo once a day (n = 12) for 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 support in vitro studies that suggest that small increases in creatinine observed in clinical studies are caused by non-pathological inhibition of the organic cation 2 (OCT2) transporter in the proximal renal tubules, which causes tubular creatinine secretion.
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 (KB) among participants for the area under the pharmacokinetic concentration-time curve (AUC) and for C max varied from ~ 20 to 40%, and the concentration at the end of the dosing interval (C t ) - 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 variability among individuals.
Suction
Dolutegravir is rapidly absorbed after ingestion, the median TC max is achieved 2-3 hours after taking the dose in the form of tablets coated with a film coat. The linearity of the pharmacokinetics of dolutegravir depends on the dose and dosage form. After oral administration, the Tivicay tablet preparation showed a generally non-linear 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 in the range from 25 mg to 50 mg.
The drug Tivikai can be taken regardless of food intake. Food increases the degree and reduces the absorption rate of dolutegravir. The bioavailability of dolutegravir depends on the food content: when eating low, moderate and high fat AUC (0-?) Dolutegravir increased by 33%, 41% and 66%, C max decreased by 46%, 52% and 67%, TC max was extended 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 obtained in vitro, dolutegravir is significantly (approximately 99.3%) bound to human plasma proteins. The apparent volume of distribution (Vd / F) after ingestion of the suspension 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, 0.4-0.5% in patients with moderate hepatic impairment, 0.8-1.0% in patients with hepatic impairment and 0.5% in patients infected with HIV-1.
Dolutegravir penetrates into the cerebrospinal fluid (CSF). In 12 previously untreated patients who received doltegravir 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 to unrelated plasma concentrations). The ratio of concentration of doltegravir in CSF to blood plasma ranged from 0.11 to 2.04%. The concentrations of dolutegravir in the CSF exceeded IC50, which confirms a median decrease in the concentration of HIV-1 RNA in the CSF, compared to a baseline of 2.2 log after 2 weeks of therapy and 3.4 log after 16 weeks of therapy (see Pharmacodynamics) .
Dolutegravir is found in the male and female genital tract. AUC in cervico-vaginal fluid, cervical and vaginal tissues was 6-10% of that in blood plasma in equilibrium. AUC in the seminal fluid was 7%, and in the rectal tissues - 17% of that in plasma at equilibrium concentration.
Metabolism
Dolutegravir is metabolized mainly by uridine-diphosphate-glucoronosyltransferase (UDF-HT) 1A1 with a negligible component of the CYP3A isoenzyme (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. Dolutegravir is slightly excreted through the kidneys in unchanged form (<1% dose). 53% of the total dose taken orally is excreted unchanged through the intestine. It is not known whether this is due to the complete or partially incomplete absorption of the drug or the elimination of the bile glucuronide conjugate, which can further decay before the formation of related compounds in the lumen of the intestine. 31% of the total dose taken internally is excreted via the kidneys in the form of the dolutegravir glucuronide ester (18.9% of the total dose), the N-dealkylated metabolite (3.6% of the total dose) and the 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) is 0.56 l / h.
Special patient groups
Children
In a pediatric study of 23 HIV-1-infected 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 of the drug Tivikai Assessment of the pharmacokinetic parameters of dolutegravir geometric mean (KB)
AUC (0-24) Ојg-h / ml C max Ојg / ml C 24 Ојg / ml
12 to <18 years of age, body weight? 40 kg 1 50 mg once a day 1 46 (43) 3.49 (38) 0.90 (59)
1 One patient with a body weight of 37 kg received dolutegravir 35 mg once a day.
Elderly patients
Group pharmacokinetic analysis of dolutegravir using data obtained in adults infected with HIV-1 showed no clinically significant effect of age on the pharmacokinetics parameters of dolutegravir. The pharmacokinetics of dolutegravir in patients over 65 years of age are limited.
Patients with renal insufficiency
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 severe renal insufficiency (CK <30 mL / min). There were no clinically significant pharmacokinetic differences between patients with severe renal insufficiency (CK <30 mL / min) and healthy volunteers. Patients with renal insufficiency do not need dose adjustment. Dolutegravir has not been studied in a group of patients on dialysis, however, differences in pharmacokinetics are not expected.
Patients with liver failure
Dolutegravir metabolized and excreted primarily by the liver. In a study that compared the 8 patients with moderate hepatic failure (class B Child-Pugh) and 8 healthy adult volunteers, the impact of a single dose of 50 mg dolutegravira was similar in the two groups. Patients with liver failure mild or moderate dose correction is not required. The influence of hepatic impairment on the pharmacokinetics of severe dolutegravira not investigated.
Polymorphism of enzymes metabolizing drugs
There is no evidence that common polymorphisms of enzymes metabolizing drugs, alter the pharmacokinetics dolutegravira in a clinically significant degree. In a meta-analysis using pharmacogenomic samples obtained in clinical trials with healthy volunteers, patients with genotypes UDP-GT1A1 (n = 7) who have low metabolism dolutegravira, dolutegravira clearance was reduced by 32%, a AUC was 46% higher compared to patients with genotypes which are associated with the normal metabolism through UDP-GT1A1 (n = 41). Polymorphism of isozymes CYP3A4, CYP3A5 and NR1I2 was not associated with differences in the pharmacokinetics of dolutegravira.
INDICATIONS
- the treatment of HIV-1 infection in adults and children 12 years and weighing 40 kg or more as part of combination antiretroviral therapy (APT).
DOSING MODE
Therapy with Tivikay should spend doctor with experience in treating HIV infection. Tivikay The drug can be administered independently from the meal.
Adult
Patients infected with HIV-1 without resistance Ini
recommended dose Tivikay drug is 50 mg 1 time per day.
In an application with efavirenz, nevirapine, tipranavir rifampicin and in combination with ritonavir Tivikay recommended dose of the drug in these patients should be 50 mg 2 times a day.
Patients infected with HIV-1 with resistance to ISI (clinically documented or suspected)
Tivikay recommended dose of the drug is 50 mg 2 times a day. The decision to use Tivikay the drug in such patients should be made taking into account the resistance to ISI.
In these patients should avoid simultaneous use with efavirenz, nevirapine, rifampicin and tipranavir combined with ritonavir.
Missed doses
If the patient has missed an appointment Tivikay drug, it should take the missed dose as soon as possible, if before the next dose is left for at least 4 hours. If prior to the next dose has less than 4 hours to a patient should not take missed dose and thus it is necessary to renew the drug according to the schedule.
Children aged 12 to 18 years and weighing 40 kg or more
The recommended dose Tivikay drug for patients who have not previously received treatment Ini (age - 12 to 18 years, body weight 40 kg or more) is 50 mg 1 time per day.
Insufficient data to recommend a dose of the drug Tivikay children between the ages of 12 and 18 with resistance to ISI.
Special patient groups
Children under 12 years of age and weighing less than 40 kg
is not enough data on safety and efficacy to recommend dose TivikayВ® children under 12 years of age or weighing less than 40 kg.
Elderly
Data on the use Tivikay drug in patients aged 65 years and older is limited. However, no data on the need for dose adjustment in elderly patients (see "Farmakokiietika" section -. "Special patient groups").
Patients with impaired renal function,
patients with mild renal insufficiency, moderate, or severe severity (CC <30 ml / min, not on dialysis) does not require a dosage adjustment. There are no data for patients on dialysis, but differences in the pharmacokinetics in this population is not expected (see "Farmakokiietika" section -. "Special patient groups").
Patients with impaired liver function
Patients with liver failure mild or moderate severity (class A or B Child-Pugh) is not required dose adjustment. There are no data regarding patients with severe hepatic insufficiency (class C by Child-Pugh) (see "Farmakokiietika" section -. "Special patient groups").
SIDE EFFECT
Adverse events reported below are listed in accordance with system-organ classification and frequency of occurrence. The frequency of occurrence is defined as follows: very common (1/10?), Common (1/100 and <1/10?), Infrequently, rarely (1/10 000 and (1/1, 000 and <1/100?)? <1/1 000), very rare (<1/10 000, including isolated cases). Frequency categories were formed on the basis of clinical trials of the drug.
The frequency of side effects
disorders of immune system
Uncommon: hypersensitivity reactions, immune reconstitution syndrome (see "Special Instructions" section.).
Violations by the psyche
often insomnia.
Disorders of the nervous system
Very common: headache.
Common: dizziness, abnormal dreams.
Violations of the gastrointestinal tract
Very common: nausea, diarrhea.
Common: vomiting, flatulence, pain in the upper abdomen.
Uncommon: abdominal pain, abdominal discomfort.
Disorders of the liver and biliary tract
Uncommon: hepatitis.
Violations of the skin and subcutaneous tissue disorders
Common: rash, pruritus.
General disorders and at the injection site
Common: fatigue.
Laboratory findings
Common: increased activity of alanine aminotransferase (ALT) and / or aspartate aminotransferase (ACT), creatine phosphokinase (CPK).
The safety profile was similar in the patient populations who have not received treatment; treated patients (excluding ISI), and patients with resistance to ISI.
Changes in laboratory parameters
During the first week of treatment Tivikay was an increase in serum creatinine concentrations, which persisted for 48 weeks. In treating patients who have not previously received treatment, the average change in 9.96 mol / L compared to the original concentration (range: -53 pmol / L to 54.8 mmol / l) was observed after 48 weeks of treatment. Increasing the concentration of creatinine concentration was comparable to that observed when using basic nucleoside analogs. This change is not considered clinically significant, because it does not reflect the change in glomerular filtration rate (see "Pharmacodynamics" section -. "Influence on kidney function").
The program for the study of drug in groups dolutegravira raltegravir and showed a slight increase of total bilirubin concentration (without clinical jaundice). These changes are not considered clinically significant, as they are likely to reflect the competitive dolutegravira clearance and unconjugated bilirubin UDP-through GT1A1 (see "Farmakokiietika" section -. "Metabolism"). Also during therapy dolutegravirom detected asymptomatic increase of CPK activity.
Use in children
on the basis of the limited data available in children aged 12 to 18 years, we can make a conclusion about the absence of additional types of adverse reactions but reactions have been observed in adults.
Co-infection with HIV and hepatitis B or C
In the phase 3 study of patients with hepatitis confection B and / or C included, provided that the initial laboratory results in liver function tests did not exceed the upper limit of normal (ULN) 5 times. Overall, the safety profile in patients coinfected with hepatitis B and / or C was the same as in patients without co-infection of hepatitis B or C, despite the fact that the frequency deviations concentration ACTi ALT was higher in the subset of patients with hepatitis coinfections B and / or C in all treatment groups. Increase in liver enzymes, corresponding to the syndrome of immune reconstitution observed in several patients coinfected with hepatitis B and / or C at the start of therapy with Tivikay, especially those who had abolished the treatment of hepatitis B (see. "Special Instructions" section).
postmarketing data
Data not available.
CONTRAINDICATIONS
- increased sensitivity to dolutegraviru or any other component of the formulation;
- Simultaneous reception with dofetilide;
- Children under 12 years of age and weighing less than 40 kg.
Carefully:
- hepatic failure, severe (class C Child-Pugh);
- while the use of medications (prescription and OTC), which may modify the action Tivikay drug or drugs whose action can change under the influence Tivikay preparation.
PREGNANCY AND LACTATION
Fertility
There are no data on the effect of the drug Tivikay on fertility in males or females. Animal studies have shown no effect dolutegravira on fertility in males or females.
Pregnancy
Appropriate and well-controlled studies of the drug Tivikay in pregnant women were not conducted. Tivikay influence of the drug on pregnant women is unknown. In reproductive toxicity studies in animals have shown that dolutegravir crosses the placenta. Tivikay drug can be used during pregnancy only if the expected benefit to the mother outweighs the potential risk to the fetus.
Breastfeeding
HIV-infected patients is recommended refusal of breastfeeding to prevent vertical transmission of HIV.
Based on the data obtained in animals, it is expected that dolutegravir will stand out in women with breast milk, although this has not been confirmed in humans.
APPLICATION FOR FUNCTIONS OF THE LIVER
Patients with mild renal insufficiency, moderate, or severe severity (CC <30 ml / min, not on dialysis) does not require a dosage adjustment. There are no data for patients on dialysis, but differences in the pharmacokinetics in this population is not expected (see "Farmakokiietika" section -. "Special patient groups").
APPLICATION FOR VIOLATIONS OF THE FUNCTION OF KIDNEYS
Patients with liver failure mild or moderate severity (class A or B Child-Pugh) is not required dose adjustment. There are no data regarding patients with severe hepatic insufficiency (class C by Child-Pugh) (see "Farmakokiietika" section -. "Special patient groups").
APPLICATION FOR CHILDREN
It is not enough data on safety and efficacy for a recommendation dose TivikayВ® children under 12 years of age or weighing less than 40 kg.
APPLICATION IN ELDERLY PATIENTS
Data on the use of the drug Tivikay in patients aged 65 years and older is limited. However, no data on the need for dose adjustment in elderly patients (see "Pharmacokinetics" section -. "Special patient groups").
SPECIAL INSTRUCTIONS
hypersensitivity reactions
In applying the ISI, including drug Tivikay, recorded hypersensitivity reactions are characterized by rash, impaired system performance and, sometimes, organ dysfunction, including liver disease. If there are signs or symptoms of hypersensitivity (including but not limited to, rash, severe or rash, accompanied by high fever, malaise, fatigue, muscle pain or joint pain, bullous lesions, lesions of the oral mucosa, conjunctivitis, swelling of the face, hepatitis, eosinophilia, angioneurotic edema), immediately cancel Tivikay use of the drug and other drugs that could cause such reactions. It is necessary to monitor the clinical condition,including indicators of liver transaminases and carry out the appropriate therapy. Delay in the termination of treatment Tivikay * any other medications that could cause similar reactions after the development of hypersensitivity reactions can lead to a condition dangerous to life.
Immune reconstitution syndrome
In HIV-infected patients with severe immune deficiency at the time of the beginning APTmozhet cause an inflammatory reaction to asymptomatic or residual opportunistic infections, which can cause serious clinical conditions, or aggravation of symptoms. Typically, such reactions have been observed within the first few weeks or months after the beginning of the APT. Typical examples of such conditions are cytomegalovirus retinitis, generalized and / or focal mycobacterial infections and pneumonia caused by Pneumocystis jiroveci (P. carinii). You must promptly evaluate any inflammatory symptoms and, if necessary, begin treatment. Autoimmune diseases (such as Graves' disease, polymyositis and Guillain-Barre syndrome) observed on a background of immune reconstitution, however, the time of primary manifestations varied,and the disease could occur many months after initiation of therapy and have an atypical course. At the beginning of therapy with Tivikay some patients coinfected with hepatitis B and / or C there was an increase in liver enzymes that reflect immune reconstitution syndrome. It is recommended to control the activity of liver enzymes in patients coinfected with hepatitis B and / or C. Need special control of the start or continuation of therapy of hepatitis B (according to current guidelines) in patients assigned treatment dolutegravirom (cm. "Side effect" section).reflecting immune reconstitution syndrome. It is recommended to control the activity of liver enzymes in patients coinfected with hepatitis B and / or C. Need special control of the start or continuation of therapy of hepatitis B (according to current guidelines) in patients assigned treatment dolutegravirom (cm. "Side effect" section).reflecting immune reconstitution syndrome. It is recommended to control the activity of liver enzymes in patients coinfected with hepatitis B and / or C. Need special control of the start or continuation of therapy of hepatitis B (according to current guidelines) in patients assigned treatment dolutegravirom (cm. "Side effect" section).
Opportunistic infections
in patients receiving drug or other Tivikay the APT, can develop opportunistic infections or other complications of HIV infection. Thus, patients should be under close clinical supervision of a physician with experience in the treatment of diseases associated with HIV.
Transmission of infection
Patients should be informed of what has not been proven to prevent the risk of transmission of HIV to others through sexual contact or through blood while taking currently available the APT, including Tivikay drug. You must continue to take the necessary precautions.
Interaction with other drugs
Not recommended simultaneous application of the drug and Tivikay etravirine, unless the patient receives simultaneously atazanavir / ritonavir, lopinavir / ritonavir or darunavir / ritonavir (cm. 'Interaction with other drugs "section).
Tivikay recommended dose of the drug is 50 mg 2 times a day, while the use of efavirenz, nevirapine, tipranavir / ritonavir or rifampicin (cm. 'Interaction with other drugs "section).
Tivikay The drug should not be administered together with antacids containing polyvalent cations. It is recommended to apply the preparation Tivikay for 2 hours before or 6 hours after application of means of the data (see. "Interaction with other drugs" section).
The drug can increase Tivikay
