Tegrad

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT TEGRA (TEGRAD)

Composition:

Active substance: dolutegravir;

1 tablet contains 50 mg of dolutegravir in the form of dolutegravir sodium;

Excipients: mannitol, microcrystalline cellulose, sodium starch glycolate (type A), povidone, sodium stearyl fumarate, Opadry II Pink 85F540088 coating: polyvinyl alcohol, titanium dioxide (E 171), polyethylene glycol, talc, iron oxide red (E 172), iron oxide yellow (E 172), iron oxide black (E 172).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: film-coated tablets, pink-colored, round, biconvex, with imprint «H» on one side and «D 13» on the other.

Pharmacotherapeutic group. Antiviral agents for systemic use. Direct-acting antiviral agents. Other antiviral agents. ATC code J05A X12.

Pharmacological properties.

Pharmacodynamics.

Mechanism of action

Dolutegravir inhibits HIV integrase by binding to the active site of the integrase enzyme and blocking the integration step of retroviral deoxyribonucleic acid (DNA), which is essential for the replication cycle of human immunodeficiency virus (HIV).

Pharmacodynamic effects

Antiviral activity in combination with other antiviral agents

No antagonistic effect was observed in vitro when dolutegravir was used in combination with other investigated antiretroviral agents: stavudine, abacavir, efavirenz, nevirapine, lopinavir, amprenavir, enfuvirtide, maraviroc, and raltegravir. In addition, no antagonistic effects were observed between dolutegravir and adefovir, and ribavirin had no apparent effect on dolutegravir activity.

Pharmacokinetics.

Pharmacokinetics (PK) of dolutegravir are similar in healthy and HIV-infected individuals. The variability of dolutegravir PK is low to moderate. In Phase I studies among healthy volunteers, the CVb% for AUC and Cmax ranged from ~20 to 40%, and for Cτ from 30 to 65% across all studies. The PK variability of dolutegravir was higher in HIV-infected patients compared to healthy volunteers. The within-patient variability (CVw%) is lower than the between-patient variability.

Absorption

Dolutegravir is rapidly absorbed after oral administration, with a median Tmax of 2–3 hours after tablet intake.

Food intake increases the extent and slows the rate of dolutegravir absorption. The bioavailability of dolutegravir depends on the composition of food: low-, medium-, and high-fat meals increased AUC(0–∞) of dolutegravir by 33%, 41%, and 66%, increased Cmax by 46%, 52%, and 67%, and prolonged Tmax to 3, 4, and 5 hours, respectively, compared to fasting conditions (Tmax of 2 hours). This increase in pharmacokinetic parameters may be clinically significant in patients with resistance to integrase inhibitor class drugs. Therefore, dolutegravir tablets are recommended to be taken with food in HIV-infected patients with resistance to integrase inhibitor class drugs (see section "Dosage and administration").

Absolute bioavailability of dolutegravir has not been determined.

Distribution

Dolutegravir has a high plasma protein binding capacity (>99%), as determined from in vitro data. The apparent volume of distribution is 17–20 L in HIV-infected patients, based on population pharmacokinetic analysis. Binding of dolutegravir to plasma proteins is independent of dolutegravir concentration. The overall blood-to-plasma ratio of radioactivity associated with the drug ranges from 0.441 to 0.535, indicating minimal binding of radioactivity to blood cellular components. The unbound fraction of dolutegravir in plasma increases with low serum albumin levels (<35 g/L), which may be observed in patients with moderate hepatic impairment.

Dolutegravir is detectable in cerebrospinal fluid (CSF). In 13 treatment-naïve patients currently on a stable regimen of dolutegravir in combination with abacavir/lamivudine, the CSF concentration of dolutegravir averaged 18 ng/mL (at the level of unbound drug concentration in plasma and above IC50).

Dolutegravir is detectable in the genital tract of men and women. AUC in cervical-vaginal secretions, cervical tissue, and vaginal tissue was 6–10% of the corresponding plasma value at steady state. AUC in semen and rectal tissue was 7% and 17% of the corresponding plasma value at steady state, respectively.

Biotransformation

Dolutegravir is primarily metabolized via glucuronidation by the UGT1A1 enzyme and to a minor extent by CYP3A. Dolutegravir circulates predominantly unchanged in plasma; renal excretion of unchanged active substance is very low (<1% of dose). 53% of the total orally administered dose is excreted unchanged in feces. It is unknown whether this is fully or partially related to unabsorbed drug or to biliary excretion of the glucuronide conjugate, which may subsequently be hydrolyzed to release the parent compound in the intestinal lumen. 32% of the total orally administered dose is excreted in urine as dolutegravir glucuronide (18.9% of total dose), N-dealkylation metabolite (3.6% of total dose), and metabolite formed by oxidation at the benzyl carbon (3% of total dose).

Interaction with medicinal products

In vitro, dolutegravir did not show direct or weak inhibition (IC50 > 50 µM) of cytochrome P450 enzymes (CYP)1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP3A, uridine diphosphate-glucuronosyltransferases (UGT)1A1 or UGT2B7, or transporters Pgp, BCRP, BSEP, OATP1B1, OATP1B3, OCT1, MATE2-K, MRP2, or MRP4. In vitro, dolutegravir did not induce CYP1A2, CYP2B6, or CYP3A4 enzymes. Based on these data, no effect of dolutegravir on the pharmacokinetics of medicinal products that are substrates of major enzymes or transporters is expected (see section "Interaction with other medicinal products and other forms of interaction").

In vitro, dolutegravir was not a substrate of human OATP1B1, OATP1B3, or OCT1.

Elimination

The elimination half-life of dolutegravir is approximately 14 hours. The apparent total clearance of the drug from plasma (CL/F) is approximately 1 L/hour in HIV-infected patients, as determined by population pharmacokinetic analysis.

Linearity/non-linearity

The pharmacokinetics of dolutegravir are dose- and formulation-dependent. After oral administration of the tablet formulation, dolutegravir generally exhibits non-linear pharmacokinetics with less than dose-proportional increases in plasma concentrations following doses from 2 to 100 mg; however, increases in dolutegravir concentration are dose-proportional when doses from 25 mg to 50 mg (for tablets) are administered. When a dose of 50 mg twice daily was administered, the 24-hour concentration was approximately doubled compared to that with 50 mg once daily.

Pharmacokinetic/pharmacodynamic relationship

In a randomized dose-finding study, HIV-1-infected patients received dolutegravir as monotherapy. Rapid and dose-dependent antiviral activity was demonstrated, with a mean reduction in HIV-1 RNA of 2.5 log10 on day 11 for the 50 mg dose. This antiviral response was maintained for 3–4 days after the last dose in the 50 mg group.

PK/PD modeling using pooled clinical trial data in patients with resistance to integrase inhibitors suggests that increasing the dose from 50 mg twice daily to 100 mg twice daily may enhance the efficacy of dolutegravir in patients with resistance to integrase inhibitors and limited treatment options due to extensive resistance to multiple classes. Clinical data on safety and efficacy of the 100 mg twice daily dose are lacking. Concomitant use with atazanavir significantly increases dolutegravir exposure and should not be used in combination with such a high dose, as safety with the resulting dolutegravir effect has not been established.

Special populations

Children

Pharmacokinetics of dolutegravir in 10 HIV-1-infected children aged 12 years and older receiving antiretroviral therapy show that an oral dose of dolutegravir 50 mg once daily results in dolutegravir concentrations comparable to those observed in adults receiving dolutegravir 50 mg once daily orally.

Elderly patients

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

Pharmacokinetic data for dolutegravir in patients over 65 years of age are limited.

Renal impairment

Renal clearance of unchanged active substance is a minor elimination pathway for dolutegravir. A pharmacokinetic study of dolutegravir was conducted in patients with severe renal impairment (CLcr < 30 mL/min) and healthy control volunteers. Dolutegravir concentrations decreased by approximately 40% in patients with severe renal impairment. The mechanism of this phenomenon is unknown. Dose adjustment is not considered necessary for patients with renal impairment. Dolutegravir tablets have not been studied in patients on dialysis.

Hepatic impairment

Dolutegravir is primarily metabolized and eliminated by the liver. A single 50 mg dose of dolutegravir was administered to 8 patients with moderate hepatic impairment (Child-Pugh class B) and 8 healthy adult controls. Although total plasma dolutegravir concentrations were similar, patients with moderate hepatic impairment showed a 1.5- to 2-fold increase in unbound dolutegravir concentrations compared to healthy controls. Dose adjustment is not considered necessary for patients with mild or moderate hepatic impairment. The effect of severe hepatic impairment on the pharmacokinetics of dolutegravir tablets has not been studied.

Polymorphism of metabolizing enzymes

There is no evidence that common polymorphisms in drug-metabolizing enzymes have a significant clinical impact on dolutegravir pharmacokinetics. In a meta-analysis using pharmacogenomic samples collected in clinical studies among healthy volunteers, individuals with UGT1A1 genotypes (n=7) associated with reduced dolutegravir metabolism had a 32% lower clearance and 46% higher AUC compared to individuals with genotypes associated with normal UGT1A1-mediated metabolism (n=41).

Gender

Population PK analysis using pooled pharmacokinetic data from Phase IIb and Phase III studies in adults did not reveal a clinically significant effect of gender on dolutegravir concentrations.

Race

Population PK analysis using pooled pharmacokinetic data from Phase IIb and Phase III studies in adults did not reveal a clinically significant effect of race on dolutegravir concentrations. Pharmacokinetics of dolutegravir after a single oral dose in Japanese patients are similar to those observed in Western (U.S.) patients.

Concomitant hepatitis B or C virus infection

Population pharmacokinetic analysis indicates that concomitant hepatitis C virus infection has no clinically significant effect on dolutegravir concentrations. Data in patients with concomitant hepatitis B virus infection are limited.

Clinical characteristics.

Indications.

Tegrag is indicated in combination with other antiretroviral medicinal products for the treatment of adults and children aged 12 years and older infected with human immunodeficiency virus (HIV).

Contraindications.

Hypersensitivity to the active substance or to any of the excipients.

Concomitant use with medicinal products having a narrow therapeutic window that are substrates of organic cation transporter 2 (OCT2), including but not limited to fampridine (also known as dalfampridine) (see section "Interaction with other medicinal products and other types of interactions").

Interaction with other medicinal products and other types of interactions.

Effect of other medicinal products on the pharmacokinetics of dolutegravir.

If resistance to integrase inhibitor class drugs exists, it is necessary to avoid any factors that may reduce dolutegravir concentrations.

Dolutegravir is primarily eliminated via metabolism mediated by the UGT1A1 enzyme. Dolutegravir is also a substrate of UGT1A3, UGT1A9, CYP3A4, P-gp, and BCRP (breast cancer resistance protein); therefore, medicinal products that induce these enzymes may reduce plasma concentrations of dolutegravir and diminish its therapeutic effect (see Table 1). Concomitant administration of dolutegravir with other medicinal products that inhibit these enzymes may increase plasma concentrations of dolutegravir (see Table 1).

The absorption of dolutegravir is reduced by certain antacid preparations (see Table 1).

Effect of dolutegravir on the pharmacokinetics of other medicinal products.

In vivo, dolutegravir does not affect midazolam—a CYP3A4 probe. Based on in vivo and in vitro data, no effect of dolutegravir on the pharmacokinetics of medicinal products that are substrates of major enzymes or transporters such as CYP3A4, CYP2C9, or P-gp is expected.

In vitro, dolutegravir inhibits the renal transporter organic cation transporter 2 (OCT2) and multidrug and toxin extrusion protein 1 (MATE-1). In vivo, patients showed a 10–14% reduction in creatinine clearance (the secretory component being dependent on OCT2 and MATE-1 transporters). In vivo, dolutegravir may increase plasma concentrations of medicinal products whose elimination depends on OCT2 or MATE-1 (such as fampridine [also known as dalfampridine], metformin) (see Table 1).

In vitro, dolutegravir inhibits renal uptake transporters, organic anion transporters (OAT1 and OAT3). Given the limited impact of tenofovir substrate on OAT pharmacokinetics in vivo, inhibition of OAT1 in vivo is unlikely. Inhibition of OAT3 has not been studied in vivo. Dolutegravir may increase plasma concentrations of medicinal products whose elimination depends on OAT3.

Established and potential interactions with specific antiretroviral and other medicinal products are listed in Table 1, where increases are indicated by the symbol ↑, decreases by ↓, no change by ↔, area under the concentration-time curve by AUC, maximum observed concentration by Cmax, and concentration at the end of the dosing interval by Cτ.

Table 1

Drug interactions

Children

Interaction studies have been conducted only in adult patients.

Special precautions for use.

Although effective suppression of the virus with antiretroviral drugs has been shown to substantially reduce the risk of sexual transmission, residual risk cannot be excluded. Preventive measures to avoid transmission of the virus should be taken in accordance with national recommendations.

Resistance to integrase inhibitor class drugs, which is of particular concern.

When considering the use of dolutegravir in cases of resistance to integrase inhibitor class drugs, it should be noted that the antiviral activity of dolutegravir is significantly reduced in patients infected with viral strains harboring secondary mutations Q148+>2 from G140A/C/S, E138A/K/T, L74I. The extent to which dolutegravir provides additional efficacy in the presence of such resistance to integrase inhibitors is unclear.

Hypersensitivity reactions.

Hypersensitivity reactions characterized by rash, constitutional findings, and sometimes organ dysfunction, including severe hepatic reactions, have been reported with dolutegravir. Dolutegravir and other suspected drugs should be discontinued immediately if signs or symptoms of hypersensitivity reactions occur (including, but not limited to, severe rash or rash accompanied by elevated liver enzymes, fever, general malaise, fatigue, muscle or joint pain, blistering, oral lesions, conjunctivitis, facial swelling, eosinophilia, or angioedema). Clinical status should be monitored, including assessment of liver aminotransferases, bilirubin, and other laboratory parameters. Delay in discontinuing dolutegravir or other suspected active substances after onset of hypersensitivity reactions may lead to life-threatening allergic reactions.

Immune reconstitution syndrome.

In HIV-infected patients with advanced immunodeficiency at the start of combination antiretroviral therapy (cART), an inflammatory response to asymptomatic or residual opportunistic pathogens may occur, leading to serious clinical manifestations or worsening of symptoms. Such reactions are typically observed within the first few weeks or months after initiation of cART. Examples include cytomegalovirus retinitis, generalized and/or focal mycobacterial infections, and Pneumocystis jirovecii pneumonia. Any inflammatory symptoms should be evaluated and appropriate treatment initiated if necessary. Autoimmune disorders (such as Graves' disease and autoimmune hepatitis) have also been reported in the context of immune reconstitution. However, the reported onset of these conditions is more variable, and such events may occur many months after starting treatment.

In some patients co-infected with hepatitis B and/or C virus, increases in biochemical markers of liver function have been observed at the beginning of treatment with dolutegravir. Monitoring of liver function tests is recommended in patients with hepatitis B and/or C co-infection. Particular caution is required when initiating or maintaining effective hepatitis B therapy if dolutegravir-based treatment is started in patients co-infected with hepatitis B virus (see section "Adverse reactions").

Opportunistic infections.

Patients should be informed that dolutegravir or any other antiretroviral agent does not cure HIV infection and that they may still develop opportunistic infections and other complications of HIV infection. Therefore, patients should remain under close clinical supervision by physicians experienced in managing HIV-associated diseases.

Drug interactions.

In patients with resistance to integrase inhibitor class drugs, factors that reduce the effect of dolutegravir should be avoided. These include concomitant use of medicinal products that reduce dolutegravir concentrations (such as magnesium/aluminum-containing antacids, iron and calcium supplements, multivitamins, stimulants, etravirine (without boosted protease inhibitors), tipranavir/ritonavir, rifampicin, St. John's wort, and certain antiepileptic drugs) (see section "Interaction with other medicinal products and other forms of interaction").

Dolutegravir increases metformin concentrations. Dose adjustment of metformin may be required at initiation and upon discontinuation of concomitant dolutegravir to maintain glycemic control (see section "Interaction with other medicinal products and other forms of interaction"). Since metformin is eliminated via the kidneys, renal function should be monitored when used concomitantly with dolutegravir. A cautious approach is recommended, as this combination may increase the risk of lactic acidosis in patients with moderate renal impairment (stage 3a [CrCl] creatinine clearance 45–59 mL/min). In such cases, consideration should be given to reducing the metformin dose (see section "Interaction with other medicinal products and other forms of interaction").

Osteonecrosis.

Although the etiology of osteonecrosis is considered multifactorial (including corticosteroid use, bisphosphonates, alcohol consumption, severe immunosuppression, and high body mass index), cases have been reported in patients with advanced HIV disease and/or long-term exposure to cART. Patients should be advised to consult a physician if they experience joint pain, stiffness, or difficulty moving.

Body weight and metabolic parameters.

Weight gain and increases in blood lipid and glucose levels may occur during antiretroviral therapy. These changes may be partly related to improved disease control and lifestyle changes. Regarding increased lipid levels, in some cases a treatment effect has been demonstrated, while there is no strong evidence linking weight gain directly to treatment. Monitoring of lipid and glucose levels should be performed in accordance with HIV treatment guidelines. Lipid disorders should be managed according to clinical standards.

Lamivudine and dolutegravir.

A combination treatment regimen using dolutegravir 50 mg once daily and lamivudine 300 mg once daily has been studied. This regimen is suitable only for the treatment of HIV-1 infection when there is no known or suspected resistance to integrase inhibitors or to lamivudine.

Tegrad contains less than 1 mmol sodium (23 mg) per tablet, i.e., essentially "sodium-free".

Use during pregnancy or breastfeeding.

Women of reproductive potential.

Women of reproductive potential should be counselled about the potential risk of neural tube defects (see below) before starting dolutegravir, and advised to use effective contraception.

If a woman plans to become pregnant, the benefits and risks of dolutegravir treatment should be evaluated.

Pregnancy.

In a Botswana birth outcomes surveillance study, a small increase in neural tube defects was observed: 7 cases of neural tube defects were reported among 3,591 births (0.19%; 95% CI 0.09%, 0.40%) to mothers who received dolutegravir-containing regimens from conception, compared with 21 cases among 19,361 births (0.11%; 95% CI 0.07%, 0.17%) to mothers who received regimens without dolutegravir from conception.

In the same study, two newborns whose mothers received dolutegravir during pregnancy had neural tube defects among 4,448 births (0.04%), compared with five cases among 6,748 births (0.07%) in mothers who received regimens without dolutegravir.

The background rate of neural tube defects in the general population ranges from 0.5 to 1 case per 1,000 live births (0.05–0.1%). Most neural tube defects occur within the first 4 weeks of embryonic development after conception (approximately 6 weeks after the last menstrual period). If pregnancy is confirmed during the first trimester while on dolutegravir treatment, the benefits and risks of continuing dolutegravir should be evaluated, and switching to alternative antiretroviral regimens should be considered, taking into account gestational age and the critical period of neural tube development.

Data analyzed from the Antiretroviral Pregnancy Registry do not indicate an increased risk of major birth defects in over 600 women who took dolutegravir during pregnancy. However, these data are insufficient to fully assess the risk of neural tube defects.

In animal reproductive toxicity studies, dolutegravir did not show adverse effects on fetal development, including neural tube defects. Dolutegravir crosses the placenta in animals.

Data from over 1,000 pregnancy outcomes with dolutegravir exposure in the second or third trimester indicate no increased risk of fetal/neonatal toxicity. Dolutegravir may be used during the second or third trimester of pregnancy only if the expected benefit to the mother outweighs the potential risk to the fetus.

Breastfeeding.

Dolutegravir is excreted in human breast milk in small amounts.

There is insufficient information on the effects of dolutegravir on newborns/infants.

HIV-infected women should not breastfeed under any circumstances to avoid transmission of HIV to the infant.

Fertility.

There are no data on the effect of dolutegravir on fertility in men and women. Animal studies did not show any effect of dolutegravir on fertility in males or females.

Ability to influence reaction speed when driving or operating machinery.

Studies specifically evaluating the effect of dolutegravir on the ability to drive or operate machinery have not been conducted. However, patients should be informed about the possibility of dizziness during treatment with dolutegravir. The patient's clinical status and adverse reaction profile should be taken into account when assessing their ability to drive or operate machinery.

Dosage and Administration

TIVICAY is prescribed by a physician experienced in the management of HIV infection.

Dosage

Adults

HIV-1–infected patients without documented or clinically suspected resistance to integrase inhibitors

The recommended dose of dolutegravir is 50 mg (1 tablet) orally once daily.

TIVICAY may be administered twice daily when coadministered with certain medications (such as efavirenz, nevirapine, tipranavir/ritonavir, or rifampicin) (see section "Interaction with other medicinal products and other forms of interaction").

HIV-1–infected patients with resistance to integrase inhibitor class drugs (documented or clinically suspected)

The recommended dose of dolutegravir is 50 mg (1 tablet) twice daily.

In cases of documented resistance including Q148 + ≥2 secondary mutations at G140A/C/S, E138A/K/T, or L74I, modeling suggests that dose escalation may be considered for patients with limited treatment options (fewer than two active agents) due to extensive cross-resistance across multiple classes.

When deciding to use dolutegravir in such patients, resistance to integrase inhibitors must be taken into account.

Missed dose

If a patient misses a dose of TIVICAY, they should take the medication as soon as possible, provided that the next dose is not due within the following 4 hours. If the next dose is due within 4 hours, the patient should not take the missed dose and should resume their normal dosing schedule.

Children aged 12 years and older

For children aged 12 to 18 years weighing at least 40 kg and infected with HIV-1 without resistance to integrase inhibitors, the recommended dose of dolutegravir is 50 mg once daily. There are insufficient data to recommend a dose of dolutegravir in adolescents with resistance to integrase inhibitors.

Elderly patients

There is limited data on the use of dolutegravir in patients aged 65 years and older. There is no evidence to suggest that elderly patients require a different dose than younger adults.

Renal impairment

No dose adjustment is necessary for patients with mild, moderate, or severe renal impairment (CrCl [creatinine clearance] < 30 mL/min) who are not on dialysis. Data in patients on dialysis are limited; however, no differences in pharmacokinetics are expected in this population.

Hepatic impairment

No dose adjustment is necessary for patients with mild or moderate hepatic impairment (Child-Pugh Class A or B). Data in patients with severe hepatic impairment (Child-Pugh Class C) are lacking; therefore, dolutegravir should be used with caution in these patients.

Administration

Oral administration.

TIVICAY can be taken with or without food. If resistance to integrase inhibitors is present, TIVICAY should be taken with food to increase its effect (particularly in patients with Q148 mutations).

Children

The product is indicated for use in children aged 12 years and older. The safety and efficacy of dolutegravir tablets in children under 12 years of age or weighing less than 40 kg have not been established. If resistance to integrase inhibitors is present, there are insufficient data to recommend the use of TIVICAY in children.

Overdose

Experience with dolutegravir overdose is limited.

Limited experience with single higher doses (up to 250 mg in healthy volunteers) did not reveal any specific symptoms or signs beyond those listed as adverse reactions.

Further management in cases of poisoning should be based on clinical judgment or in accordance with recommendations from the relevant national toxicology center. There is no specific antidote for dolutegravir overdose. In the event of overdose, the patient should receive symptomatic treatment with appropriate monitoring, if necessary. Since dolutegravir is highly protein-bound, significant removal by hemodialysis is unlikely.

Adverse reactions.

Safety profile overview

The most severe adverse reaction observed in individual patients was hypersensitivity reaction, including rash and severe hepatic effects (see section "Special precautions"). The most frequently occurring adverse reactions during treatment were nausea (13%), diarrhea (18%), and headache (13%).

List of adverse reactions

Adverse reactions considered possibly related to the use of dolutegravir are listed by system organ classes and absolute frequency of occurrence. Frequency is defined as follows: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1000 to <1/100), rare (≥1/10,000 to <1/1000), very rare (<1/10,000).

Table 2

Adverse reactions

* see below in the section "Some adverse reactions";

** in combination with increased transaminase levels.

Some adverse reactions

Changes in laboratory biochemical test parameters

Increased serum creatinine levels occurred during the first week of treatment with dolutegravir and persisted for 48 weeks. After 48 weeks of treatment, the mean change from baseline was 9.96 µmol/L. The increase in creatinine levels was similar across different background regimens. These changes are not considered clinically significant, as they do not reflect changes in glomerular filtration rate.

Concurrent hepatitis B or C virus infection

In Phase III studies, patients with concurrent hepatitis B and/or C virus infection were allowed to participate provided that baseline liver function biochemical parameters did not exceed five times the upper limit of normal (ULN). Overall, the safety profile in patients with concurrent hepatitis B and/or C virus infection was similar to that in patients without concurrent hepatitis B or C virus infection, although abnormal AST and ALT values were higher in the subgroup with concurrent hepatitis B and/or C virus infection across all treatment groups. Elevations in liver function biochemical parameters consistent with immune reconstitution syndrome were observed in some patients with concurrent hepatitis B and/or C virus infection at the initiation of dolutegravir treatment, particularly in those who had discontinued hepatitis B treatment (see section "Special precautions").

Immune Reconstitution Syndrome

In HIV-infected patients with advanced immunodeficiency at the start of combination antiretroviral therapy (cART), an inflammatory response to asymptomatic or residual opportunistic infections may occur. Autoimmune disorders (such as Graves' disease and autoimmune hepatitis) have also been reported; however, the reported time to onset of such disorders is more variable, and these events may occur many months after initiation of treatment (see section "Special precautions").

Metabolic parameters

During antiretroviral therapy, increases in body weight and elevations in blood lipid and glucose levels may occur (see section "Special precautions").

Children

Based on limited data in children aged 12 years and older with body weight of at least 40 kg, no additional types of adverse reactions were observed beyond those identified in adults.

Reporting of adverse reactions

Reporting of adverse reactions after drug registration is of great importance. It enables ongoing monitoring of the benefit-risk balance of the medicinal product. Medical and pharmaceutical professionals, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of efficacy through the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua/.

Shelf life. 3 years.

Storage conditions.

Store at temperatures not exceeding 30 ºC and protect from moisture. Keep out of reach of children.

Packaging. 30 tablets in a container; 1 container in a cardboard box.

10 tablets in a blister; 8 blisters in a cardboard box.

Prescription status. Prescription only.

Manufacturer. Hetero Labs Limited.

Manufacturer's address and location of operations.

Unit III, Formulation Plot No 22 - 110 IDA, Jeedimetla, Hyderabad, 500 055 Telangana, India.