Tivicay^® (Tablets) Instructions for Use

Marketing Authorization Holder

ViiV Healthcare UK, Limited (United Kingdom)

Manufactured By

Glaxo Operations UK Limited (United Kingdom)

Or

Servier Rus, LLC (Russia)

Packaging and Quality Control Release

Glaxo Wellcome, S.A. (Spain)

Or

SERVIER RUS, LLC (Russia)

ATC Code

J05AJ03 (Dolutegravir)

Active Substance

Dolutegravir (Rec.INN registered by WHO)

Dosage Form

Tivicay®

Film-coated tablets, 50 mg: 30 pcs.

Dosage Form, Packaging, and Composition

Film-coated tablets yellow, round, biconvex, with the inscription "SV 572" engraved on one side and "50" on the other side.

Excipients : mannitol – q.s. (up to 145.4 mg), microcrystalline cellulose – 60 mg, povidone K29/32 – 15 mg, sodium carboxymethyl starch – 21 mg, sodium stearyl fumarate – 6 mg; film coating: Opadry^® II yellow 85F92461 – 9 mg [polyvinyl alcohol (partially hydrolyzed) – 40% w/w, titanium dioxide – 23.45% w/w, macrogol (polyethylene glycol) – 20.2% w/w, talc – 14.8% w/w, iron oxide yellow – 1.55% w/w].

30 pcs. – bottles (1) – cardboard packs.

Clinical-Pharmacological Group

Antiviral drug active against HIV

Pharmacotherapeutic Group

Systemic antiviral agents; direct-acting antiviral agents; integrase inhibitors

Pharmacological Action

Mechanism of action

Dolutegravir inhibits HIV integrase by binding to the active site of integrase and blocking the strand transfer step during retroviral deoxyribonucleic acid (DNA) integration, which is necessary for the HIV replication cycle. In vitro, Dolutegravir dissociates slowly from the active site of the wild-type integrase-DNA complex (T_1/2 71 hours).

Pharmacodynamic effects

In a randomized dose-ranging study in HIV-1-infected patients receiving dolutegravir monotherapy, rapid and dose-dependent antiviral activity was observed. Mean reductions in HIV-1 RNA from baseline at Day 11 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 in the group of patients taking 50 mg of dolutegravir.

Antiviral activity in cell culture

In peripheral blood mononuclear cells (PBMCs) infected with the BaL strain of HIV-1 or the NL432 strain of HIV-1, IC50 (concentration inhibiting replication by 50%) values for dolutegravir were 0.51 nM and 0.53 nM, respectively. In MT-4 cells infected with the IIIB strain of HIV-1 and incubated with dolutegravir for 4 or 5 days, IC50 values of 0.71 and 2.1 nM were obtained. In two in vitro biochemical DNA strand transfer assays using purified HIV-1 integrase and pre-processed DNA substrate, IC50 values of 2.7 nM and 12.6 nM were obtained.

In a viral integrase susceptibility assay using the integrase coding region from 13 clinically diverse subtype B isolates, Dolutegravir demonstrated antiviral activity similar to that against laboratory strains, with a mean IC50 of 0.52 nM. In a PBMC assay of a panel consisting of 24 clinical isolates of HIV-1 [group M (subtypes A, B, C, D, E, F, and G) and group O], and 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 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 anti-HIV antiviral activity showed antagonism to dolutegravir (in vitro evaluation was conducted in combination with stavudine, abacavir, efavirenz, nevirapine, lopinavir, amprenavir, enfuvirtide, maraviroc, adefovir, and raltegravir, selected in a checkerboard pattern). Furthermore, antiviral drugs without typical anti-HIV activity (ribavirin) had no apparent effect on dolutegravir activity.

Effect of human serum and serum proteins

In vitro studies confirmed a 75-fold change (FC) in dolutegravir IC50 in the presence of 100% human serum (by extrapolation method), and the protein binding-adjusted IC90 (PA-IC90) in PBMCs was 64 ng/ml. The steady-state concentration of dolutegravir after a single 50 mg dose in integrase inhibitor-naive patients was 1.20 µg/ml, thus 19 times higher than the established PA-IC90.

In vitro resistance

HIV-1 wild-type isolates During 112-day passage of the IIIB strain, no viruses with high-level resistance to dolutegravir were detected; a maximum 4.1-fold change was observed in passaged groups of resistant viruses with S153Y and S153F substitutions at conserved positions of the integrase gene. Passage of the HIV-1 wild-type NL-432 strain in the presence of dolutegravir led to the selection of the E92Q substitution (passaged virus group with FC =3.1) and G193E (passaged virus group with FC = 3.2) on day 56. Additional passage of wild-type subtypes B, C, and A/G 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 (RTIs) and protease inhibitors (PIs): Dolutegravir demonstrated equivalent activity against 2 non-nucleoside (NN)-RTI-resistant, 3 nucleoside (N)-RTI-resistant, and 2 PI-resistant mutant HIV-1 clones (1 with triple and 1 with six-fold resistance) compared to the wild-type strain.

HIV-1 strains resistant to integrase inhibitors 60 mutant HIV-1 isolates resistant to integrase inhibitors (INSTIs) (28 with a single substitution and 32 with 2 or more substitutions) were generated from the NL432 wild-type virus by site-directed mutagenesis. Dolutegravir demonstrated antiviral activity (susceptibility) against HIV with FC < 5 against 27 of 28 INSTI-resistant mutant viruses with a single substitution, including T66A/I/K, E92Q/V, Y143C/H/R, Q148H/K/R, and N155H, whereas for raltegravir and elvitegravir it was observed against 17/28 and 11/21 tested mutant viruses with FC < 5, respectively. Furthermore, of the 32 INSTI-resistant mutant viruses with 2 or more substitutions, 23 of 32 demonstrated FC < 5 for dolutegravir compared to FC < 5 for 4 of 32 for raltegravir and FC < 5 for 2 of 25 tested viruses for elvitegravir.

HIV-2 strains resistant to INSTIs Viruses were generated by site-directed mutagenesis from HIV-2 isolates obtained from HIV-2-infected patients who received raltegravir and experienced virological failure. Overall, FCs for HIV-2 were similar to FCs for HIV-1 observed with a similar set of mutations. The dolutegravir FC was < 5 against 4 HIV-2 viruses (S163D, G140A/Q148R, A153G/N155H/S163G, and E92Q/T97A/N155H/S163D); for E92Q/N155H the dolutegravir FC was 8.5, and for G140S/Q148R the dolutegravir FC was 17. Dolutegravir, raltegravir, and elvitegravir showed equivalent activity against HIV-2 with the site-directed S163D mutation as against the wild type, and for the remaining mutant HIV-2 viruses, the raltegravir FC ranges were 6.4-20, and the elvitegravir FC ranges were 22-640.

Clinical isolates from patients with virological failure on raltegravir 30 clinical isolates with genotypic and phenotypic resistance to raltegravir (median FC >81) were tested for susceptibility to dolutegravir (median FC 1.5) using the Monogram Biosciences PhenoSense assay. The median dolutegravir FC for isolates with substitutions at positions G140S + Q148H was 3.75; G140S + Q148R— 13.3; T97A + Y143R — 1.05 and N155H — 1.37. 705 raltegravir-resistant isolates obtained from patients receiving raltegravir were analyzed for susceptibility to dolutegravir using the Monogram Biosciences PhenoSense assay. Dolutegravir showed FC < 10 against 93.9% of the 705 clinical isolates.

In vivo resistance: INSTI-naive patients

No INSTI resistance mutations or treatment-emergent resistance to the nucleoside reverse transcriptase inhibitor (NRTI) backbone were observed in treatment-naive patients who took 50 mg of Tivicay^® once daily (studies SPRING-1, SPRING-2, and SINGLE). In the SAILING study in INSTI-naive patients receiving Tivicay^® (n = 354 in the dolutegravir group), treatment-emergent INSTI resistance was observed at Week 48 in 4 of 17 patients with virological failure receiving Dolutegravir. Two of the 4 patients had the unique R263K substitution in the integrase gene with a maximum FC of 1.93, 1 patient had the polymorphic integrase substitution V151V/I with a maximum FC of 0.92, and 1 patient had pre-existing integrase mutations and was suspected of prior INSTI exposure or infection with an INSTI-resistant virus.

In vivo resistance: INSTI-experienced patients

The VIKING-3 study evaluated Tivicay^® (plus optimized background therapy) in patients with existing INSTI resistance. Up to Week 24, 36 of 183 patients had protocol-defined virological failure (PDVF). Of these, paired baseline and PDVF resistance data were available for 31 patients, and 16/31 (52%) had treatment-emergent mutations. The following treatment-emergent 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). 14 of the 16 patients with treatment-emergent virus mutations had a Q148 mutation at baseline or in their history.

Effect on ECG parameters

In a randomized, crossover, placebo-controlled clinical study, 42 healthy volunteers received a single dose of placebo, 250 mg dolutegravir suspension (exposure approximately 3 times the exposure of the 50 mg once daily dose at steady state), and moxifloxacin (400 mg, active control) in random order. Dolutegravir did not cause QT interval prolongation over 24 hours after drug administration. After baseline and placebo correction, the maximum mean change in QT based on Fridericia’s correction (QTcF) was 1.99 ms (upper bound of the 1-sided 95% confidence interval — 4.53 ms).

Effect on renal function

The effect of Tivicay^® on serum creatinine clearance (CrCl), iohexol-based glomerular filtration rate (GFR), and para-aminohippurate-based effective renal plasma flow (ERPF) was evaluated in an open-label, randomized, placebo-controlled, three-group study in 37 healthy volunteers who took 50 mg Tivicay^® once daily (n= 12), 50 mg twice daily (n = 13), or placebo once daily (n = 12) for 14 days. A moderate decrease in CrCl was observed with dolutegravir during the first week of treatment, consistent with the decrease observed in clinical trials. At both doses, Dolutegravir had no significant effect on GFR or ERPF. These data support in vitro studies suggesting that the small increases in creatinine observed in clinical trials are caused by non-pathological inhibition of the organic cation transporter 2 (OCT2) in the proximal renal tubules, which mediates the tubular secretion of creatinine.

Pharmacokinetics

The pharmacokinetics of dolutegravir are similar in healthy volunteers and HIV-infected patients. The pharmacokinetic variability of dolutegravir was low to moderate. In Phase 1 studies in healthy volunteers, the inter-subject coefficient of variation (CV) for the area under the concentration-time curve (AUC) and for C_max ranged from ~20 to 40%, and for the concentration at the end of the dosing interval (C_t) from 30 to 65%. The inter-subject pharmacokinetic variability of dolutegravir was higher in HIV-infected patients than in healthy volunteers. Intra-individual variability in pharmacokinetic parameters was lower than inter-individual variability.

Absorption

Dolutegravir is rapidly absorbed after oral administration, with a median T_max achieved 2-3 hours after dosing in the film-coated tablet formulation. The linearity of dolutegravir pharmacokinetics is dose- and formulation-dependent. After oral administration, Tivicay^® tablets generally exhibited non-linear pharmacokinetics, with less than dose-proportional increases in plasma exposure from 2 to 100 mg, but the increase in dolutegravir exposure was dose-proportional in the range from 25 mg to 50 mg.

Tivicay^® can be taken with or without food. Food increases the extent and decreases the rate of absorption of dolutegravir. The bioavailability of dolutegravir is food-dependent: with low, moderate, and high-fat meals, the AUC_(0-∞) of dolutegravir increased by 33%, 41%, and 66%, C_max decreased by 46%, 52%, and 67%, and T_max was prolonged to 3, 4, and 5 hours compared to 2 hours under fasting conditions, respectively. These increases are not considered clinically significant.

The absolute bioavailability of dolutegravir has not been determined.

Distribution

According to in vitro data, Dolutegravir is highly bound (approximately 99.3%) to human plasma proteins. The apparent volume of distribution (Vd/F) after oral administration of the suspension is approximately 12.5 L. The binding of dolutegravir to plasma proteins was concentration-independent. The ratios of total radiolabeled drug concentration in blood and plasma were 0.441-0.535, indicating minimal association of the radiolabeled drug with cellular blood components. The free fraction of dolutegravir in 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 severe hepatic impairment, and 0.5% in HIV-1-infected patients.

Dolutegravir penetrates into the cerebrospinal fluid (CSF). In 12 treatment-naive patients receiving a regimen of Dolutegravir and abacavir/lamivudine for 16 weeks, the mean concentration of dolutegravir in CSF was 15.4 ng/ml at week 2 and 12.6 ng/ml at week 16, with a range from 3.7 to 23.2 ng/ml (comparable to the unbound plasma concentration). The ratio of dolutegravir concentration in CSF to plasma ranged from 0.11 to 2.04%. Dolutegravir concentrations in CSF exceeded the IC50, supporting a median reduction in HIV-1 RNA in CSF from baseline of 2.2 log after 2 weeks of therapy and 3.4 log after 16 weeks of therapy (see the “Pharmacodynamics” subsection).

Dolutegravir is detected in the male and female genital tracts. The AUC in cervicovaginal fluid, cervical, and vaginal tissues was 6-10% of that in plasma at steady state. The AUC in seminal fluid was 7%, and in rectal tissues was 17% of that in plasma at steady-state concentration.

Metabolism

Dolutegravir is primarily metabolized by uridine diphosphate-glucuronosyltransferase (UGT)1A1 with a minor component from the CYP3A isoenzyme (9.7% of the total administered dose in a human mass balance study). Dolutegravir is the major circulating compound in plasma. Dolutegravir is minimally excreted unchanged in the urine (< 1% of the dose). 53% of the total orally administered dose is excreted unchanged in the feces. It is unknown whether this is due to complete or partial incomplete absorption of the drug or biliary excretion of the glucuronide conjugate, which may further break down to form related compounds in the intestinal lumen. 31% of the total orally administered dose is excreted in the urine as dolutegravir glucuronide (18.9% of the total dose), an N-dealkylated metabolite (3.6% of the total dose), and a metabolite formed by oxidation of the benzylic carbon (3.0% of the total dose).

Elimination

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

Special patient populations

Children

In a pediatric study including 23 antiretroviral treatment-experienced, HIV-1-infected adolescents aged 12 to 18 years, dolutegravir pharmacokinetic data from 10 children showed that a daily dose of 50 mg of dolutegravir resulted in similar dolutegravir exposure in children and adolescents as in adults receiving 50 mg of dolutegravir once daily.

Pharmacokinetic parameters in children (n=10)

¹One patient with a body weight of 37 kg received Dolutegravir 35 mg once daily.

Elderly patients

A population pharmacokinetic analysis of dolutegravir using data from HIV-1-infected adults showed no clinically significant effect of age on dolutegravir pharmacokinetic parameters. Data on dolutegravir pharmacokinetics in patients over 65 years of age are limited.

Patients with renal impairment

Renal clearance of unchanged drug is a minor pathway for dolutegravir elimination. A pharmacokinetic study of dolutegravir was conducted in patients with severe renal impairment (CrCl < 30 ml/min). No clinically significant pharmacokinetic differences were observed between patients with severe renal impairment (CrCl < 30 ml/min) and healthy volunteers. No dose adjustment is required for patients with renal impairment. Dolutegravir has not been studied in patients on dialysis, however, no differences in pharmacokinetics are expected.

Patients with hepatic impairment

Dolutegravir is metabolized and eliminated primarily by the liver. In a study comparing 8 patients with moderate hepatic impairment (Child-Pugh class B) and 8 healthy adult volunteers, exposure to a single 50 mg dose of dolutegravir was similar in the two groups. No dose adjustment is required for patients with mild or moderate hepatic impairment. 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 polymorphisms of drug-metabolizing enzymes alter the pharmacokinetics of dolutegravir in a clinically significant manner. In a meta-analysis using pharmacogenomic samples obtained from clinical studies involving healthy volunteers, in patients with UGT1A1 genotypes (n = 7) who had weak metabolism of dolutegravir, the clearance of dolutegravir was reduced by 32%, and the AUC was 46% higher compared to patients with genotypes associated with normal metabolism via UGT1A1 (n = 41). Polymorphism of the CYP3A4, CYP3A5, and NR1I2 isoenzymes was not associated with differences in the pharmacokinetics of dolutegravir.

Indications

• Treatment of HIV-1 infection in adults and children aged 12 years and older weighing 40 kg and above as part of combined antiretroviral therapy (ART).

ICD codes

Dosage Regimen

Treatment with Tivicay^® should be administered by a physician experienced in the management of HIV infection. Tivicay^® can be taken with or without food.

Adults

Patients infected with HIV-1 without INSTI resistance

The recommended dose of Tivicay^® is 50 mg once daily.

When used concomitantly with efavirenz, nevirapine, rifampicin, and 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 INSTI resistance (documented or clinically suspected)

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

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

Missed dose

If a patient misses a dose of Tivicay^®, they should take the missed dose as soon as possible if it is at least 4 hours before the next dose is due. If it is less than 4 hours until the next dose, the patient should not take the missed dose and should resume taking the medication according to the schedule.

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

The recommended dose of Tivicay^® for patients who have not previously received treatment with an INSTI (age 12 to 18 years, weight 40 kg and above) is 50 mg once daily.

There is insufficient data to recommend a dose of Tivicay^® for children aged 12 to 18 years with INSTI resistance.

Special patient groups

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

There is insufficient safety and efficacy data to recommend a dose of Tivicay^® for 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 indicating the need for dose adjustment in elderly patients (see section “Pharmacokinetics” – “Special patient groups”).

Patients with renal impairment

No dose adjustment is required for patients with mild, moderate, or severe renal impairment (CrCl <30 mL/min, not on dialysis). There are no data for patients on dialysis, but no differences in pharmacokinetics are expected in this population (see section “Pharmacokinetics” – “Special patient groups”).

Patients with hepatic impairment

No dose adjustment is required for patients with mild or moderate hepatic impairment (Child-Pugh class A or B). There are no data regarding patients with severe hepatic impairment (Child-Pugh class C) (see section “Pharmacokinetics” – “Special patient groups”).

Adverse Reactions

The adverse events listed below are categorized by system organ class and frequency of occurrence. Frequency is defined as follows: very common (≥ 1/10), common (≥ 1/100 and < 1/10), uncommon (≥ 1/1,000 and < 1/100), rare (≥ 1/10,000 and < 1/1,000), very rare (< 1/10,000, including isolated cases). Frequency categories were formed based on clinical trials of the drug.

Frequency of adverse reactions

Immune system disorders

Uncommon: hypersensitivity reaction, immune reconstitution inflammatory syndrome (see section “Special Precautions”).

Psychiatric disorders

Common: insomnia.

Nervous system disorders

Very common: headache.

Common: dizziness, abnormal dreams.

Gastrointestinal disorders

Very common: nausea, diarrhea.

Common: vomiting, flatulence, upper abdominal pain.

Uncommon: abdominal pain, abdominal discomfort.

Hepatobiliary disorders

Uncommon: hepatitis.

Skin and subcutaneous tissue disorders

Common: rash, pruritus.

General disorders and administration site conditions

Common: fatigue.

Laboratory parameters

Common: increased ALT and/or AST, creatine phosphokinase (CPK).

The safety profile was similar in treatment-naive patient populations; treatment-experienced patients (except for INSTIs), and patients with INSTI resistance.

Changes in laboratory parameters

During the first week of treatment with Tivicay^®, an increase in serum creatinine concentration was observed, which persisted for 48 weeks. In the treatment of previously untreated patients, a mean change of 9.96 µmol/L from baseline (range: -53 µmol/L to 54.8 µmol/L) was observed after 48 weeks of treatment. The increase in creatinine concentration was comparable to that observed with the main NRTIs. This change is not considered clinically significant as it does not reflect a change in glomerular filtration rate (see section “Pharmacodynamics” – “Effect on renal function”).

In the drug study program, minor increases in total bilirubin concentration (without clinical jaundice) were observed in the dolutegravir and raltegravir groups. These changes are not considered clinically significant, as they likely reflect the competitive clearance of dolutegravir and unconjugated bilirubin via UGT1A1 (see section “Pharmacokinetics” – “Metabolism”). Asymptomatic increases in CPK activity were also recorded during dolutegravir therapy.

Use in children

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

HIV and hepatitis B or C co-infection

Phase 3 studies included patients with hepatitis B and/or C co-infection, provided that baseline liver function test results did not exceed 5 times the upper limit of normal (ULN). Overall, the safety profile in patients with hepatitis B and/or C co-infection was the same as in patients without hepatitis B or C co-infection, although the frequency of AST and ALT abnormalities was higher in the subgroup of patients with hepatitis B and/or C co-infection across all treatment groups. Increases in liver enzymes consistent with immune reconstitution inflammatory syndrome were observed in several patients with hepatitis B and/or C co-infection at the start of Tivicay^® therapy, especially in those who discontinued hepatitis B treatment (see section “Special Precautions”).

Post-marketing data

No data available.

Contraindications

• Hypersensitivity to dolutegravir or any other component of the drug;
• Concomitant use with dofetilide;
• Children under 12 years of age and weighing less than 40 kg.

With caution

• Severe hepatic impairment (Child-Pugh class C);
• When used concomitantly with medicinal products (prescription and over-the-counter) that may alter the effect of Tivicay^®, or medicinal products whose effect may be altered by Tivicay^®.

Use in Pregnancy and Lactation

Fertility

There are no data on the effect of Tivicay^® on fertility in men or women. Animal studies have shown no effect of dolutegravir on fertility in males or females.

Pregnancy

Adequate and well-controlled studies of Tivicay^® in pregnant women have not been conducted. The effect of Tivicay^® on pregnancy in women is unknown. In animal reproductive toxicity studies, Dolutegravir was shown to cross the placenta. Tivicay^® should be used during pregnancy only if the expected benefit to the mother outweighs the potential risk to the fetus.

Breastfeeding period

HIV-infected patients are recommended to avoid breastfeeding to prevent vertical transmission of HIV infection.

Based on data from animals, it is expected that Dolutegravir will be excreted in human milk, although this has not been confirmed in humans.

Use in Hepatic Impairment

No dose adjustment is required for patients with mild or moderate hepatic impairment (Child-Pugh class A or B). There are no data regarding patients with severe hepatic impairment (Child-Pugh class C) (see section “Pharmacokinetics” – “Special patient groups”).

Use in Renal Impairment

No dose adjustment is required for patients with mild, moderate, or severe renal impairment (CrCl <30 mL/min, not on dialysis). There are no data for patients on dialysis, but no differences in pharmacokinetics are expected in this population (see section “Pharmacokinetics” – “Special patient groups”).

Pediatric Use

There is insufficient safety and efficacy data to recommend a dose of Tivicay^® for children under 12 years of age or weighing less than 40 kg.

Geriatric Use

Data on the use of Tivicay^® in patients aged 65 years and older are limited. However, there are no data indicating the need for dose adjustment in elderly patients (see section “Pharmacokinetics” – “Special patient groups”).

Special Precautions

Hypersensitivity reactions

Hypersensitivity reactions have been reported with the use of INSTIs, including Tivicay^®, characterized by rash, systemic manifestations, and sometimes organ dysfunction, including liver damage. If signs or symptoms of hypersensitivity occur (including, but not limited to, severe rash or rash accompanied by fever, general malaise, fatigue, muscle or joint pain, bullous lesions, oral mucosa lesions, conjunctivitis, facial edema, hepatitis, eosinophilia, angioedema), Tivicay^® and other drugs that could cause such reactions should be discontinued immediately. Clinical status, including liver aminotransferases, should be monitored and appropriate therapy instituted. Delay in stopping treatment with Tivicay^® or other drugs that could cause such reactions after the onset of hypersensitivity reactions may lead to life-threatening conditions.

Immune reconstitution inflammatory syndrome

In HIV-infected patients with severe immunodeficiency, an inflammatory response to asymptomatic or residual opportunistic infections may occur during the initiation of ART, which can cause serious clinical conditions or worsening of symptoms. Typically, such reactions have been observed within the first few weeks or months after starting ART. Typical examples of such conditions are cytomegalovirus retinitis, generalized and/or focal mycobacterial infections, and pneumonia caused by Pneumocystis jiroveci (P. carinii). Any inflammatory symptoms should be evaluated promptly and treatment initiated if necessary. Autoimmune diseases (such as Graves’ disease, polymyositis, and Guillain-Barré syndrome) have been observed in the context of immune reconstitution, although the timing of initial manifestations varied, and the disease could occur many months after starting therapy and have an atypical course. At the start of Tivicay^® therapy, some patients with hepatitis B and/or C co-infection experienced increased liver enzyme activity, reflecting immune reconstitution inflammatory syndrome. Monitoring of liver enzymes is recommended in patients with hepatitis B and/or C co-infection. Particular attention should be paid to the initiation or continuation of hepatitis B therapy (according to current guidelines) in patients prescribed dolutegravir treatment (see section “Adverse Reactions”).

Opportunistic infections

Patients receiving Tivicay^® or other ART 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 diseases.

Transmission of infection

Patients should be informed that it has not been proven that currently available ART, including Tivicay^®, prevents the risk of sexual or blood-borne transmission of HIV to others. Necessary precautions must continue to be taken.

Drug interactions

Concomitant use of Tivicay^® and etravirine is not recommended unless the patient is also receiving atazanavir / ritonavir, lopinavir / ritonavir, or darunavir / ritonavir (see section “Drug Interactions”).

The recommended dose of Tivicay^® is 50 mg twice daily when used concomitantly with efavirenz, nevirapine, tipranavir / ritonavir, or rifampicin (see section “Drug Interactions”).

Tivicay^® should not be administered together with antacids containing polyvalent cations. It is recommended to take Tivicay^® 2 hours before or 6 hours after taking these agents (see section “Drug Interactions”).

Tivicay^® may increase metformin concentrations. Patients should be monitored during therapy, and dose adjustments of metformin may be required (see section “Drug Interactions”).

Resistance to integrase inhibitors of particular importance

When deciding to use dolutegravir in the presence of INSTI resistance, it should be taken into account that the activity of dolutegravir is significantly reduced 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 INSTI resistance remains unclear.

Osteonecrosis

Although the etiology of this condition is multifactorial (including the use of corticosteroids, bisphosphonates, alcohol consumption, severe immunosuppression, high body mass index), cases of osteonecrosis have been reported most frequently in patients with advanced HIV disease and/or on long-term combined ART. Patients should consult their doctor if they experience joint pain and stiffness or difficulty moving.

Effect on ability to drive and operate machinery

No studies have been conducted on the effect of Tivicay^® on the ability to drive and operate machinery. The patient’s clinical condition and the adverse reaction profile of Tivicay^® should be considered when assessing the patient’s ability to drive or operate machinery.

Overdose

Symptoms

Data on overdose with Tivicay^® are limited.

Limited experience with higher single doses (up to 250 mg in healthy volunteers) revealed no specific symptoms or signs other than those described in the “Adverse Reactions” section.

Treatment

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

Drug Interactions

Effect of dolutegravir on the pharmacokinetics of other drugs

In vitro, Dolutegravir demonstrates no direct inhibition or weak inhibition (IC50 > 50 µM) of the cytochrome P450 system isoenzymes CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP3A, UGT1A1, or UGT2B7, or the transporters P-gp, BCRP, OATP1B1, OATP1B3, OAT1, or MRP2. In vitro, Dolutegravir does not induce CYP1A2, CYP2B6, or CYP3A4 isoenzymes. In vivo, Dolutegravir has no effect on midazolam, a CYP3A4 activity marker. Based on these data, Tivicay^® is not expected to affect the pharmacokinetics of drugs that are substrates of these enzymes or transporters (e.g., reverse transcriptase inhibitors or protease inhibitors, abacavir, zidovudine, maraviroc, opioid analgesics, antidepressants, statins, azole antifungals, proton pump inhibitors, drugs for erectile dysfunction, acyclovir, valacyclovir, sitagliptin, adefovir). In drug interaction studies, Dolutegravir had no clinically significant effect on the pharmacokinetics of the following drugs: tenofovir, methadone, efavirenz, lopinavir, atazanavir, darunavir, etravirine, fosamprenavir, rilpivirine, telaprevir, and oral contraceptives containing norgestimate and ethinyl estradiol.

In vitro, Dolutegravir inhibited renal OCT2. Based on these observations, it was concluded that Dolutegravir may increase plasma concentrations of drugs whose elimination depends on OCT2 (dofetilide, metformin) (see Table 1).

Effect of Other Agents on the Pharmacokinetics of Dolutegravir

Dolutegravir is eliminated primarily via UGT1A1 metabolism. Dolutegravir is also a substrate of UGT1A3, UGT1A9, CYP3A4, P-gp, and BCRP; therefore, drugs that induce these enzymes may theoretically reduce dolutegravir plasma concentrations and diminish the therapeutic effect of Tivicay^®.

Concomitant use of Tivicay^® and other drugs that inhibit UGT1A1, UGT1A3, UGT1A9, CYP3A4, and/or P-gp may increase dolutegravir plasma concentrations (see Table 1). Efavirenz, nevirapine, rifampicin, and tipranavir co-administered with ritonavir significantly reduced dolutegravir plasma concentrations and, therefore, a dose adjustment of Tivicay^® to 50 mg twice daily is necessary. Etravirine also reduced dolutegravir plasma concentrations, but the effect of etravirine was attenuated by the concomitant use of the CYP3A4 inhibitors lopinavir/ritonavir, darunavir/ritonavir, and is expected to be attenuated by atazanavir/ritonavir. Thus, no dose adjustment of dolutegravir is required when co-administered with etravirine and lopinavir/ritonavir, darunavir/ritonavir, or atazanavir/ritonavir. Another inducer, fosamprenavir, co-administered with ritonavir, reduced dolutegravir plasma concentrations, but no dose adjustment of Tivicay^® is required. Caution and clinical monitoring are advised when prescribing these combinations to patients with resistance to integrase inhibitors (see Table 1). An interaction study with the UGT1A1 inhibitor atazanavir did not show a clinically significant increase in dolutegravir plasma concentrations. Tenofovir, ritonavir, lopinavir/ritonavir, darunavir/ritonavir, rilpivirine, boceprevir, telaprevir, prednisone, rifabutin, and omeprazole had no effect or a minimal effect on the pharmacokinetics of dolutegravir, so no dose adjustment of Tivicay^® is required when co-administered with these drugs.

A number of interactions with other drugs are presented in Table 1. Recommendations are based either on drug interaction studies or on predicted interactions due to the expected magnitude of the interaction and the likelihood of developing serious adverse events or loss of efficacy.

Table 1. Drug Interactions

Abbreviations: ↑ — increase; ↓ — decrease; ↔ — no significant changes; C_max — observed maximum concentration, C_trough — concentration at the end of the dosing interval.

Storage Conditions

Store at a temperature not exceeding 30°C (86°F). Keep out of reach of children.

Shelf Life

Shelf life – 2 years.

Dispensing Status

By prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.