INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT DOLUTEGRAVIR 50 MG

Composition:

Active substance: dolutegravir;

One film-coated tablet contains dolutegravir sodium equivalent to 50 mg of dolutegravir;

Excipients: mannite (E 421), microcrystalline cellulose, sodium starch glycolate, povidone, sodium stearyl fumarate;

Coating Opadry II Pink (85F540358): polyvinyl alcohol partially hydrolyzed, titanium dioxide (E 171), macrogol, talc, iron oxide red (E 172).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: pink-colored, round, biconvex, film-coated tablets, engraved with «I77» on one side and smooth on the other.

Pharmacotherapeutic group. Antiviral agents for systemic use. Direct-acting antiviral agents. Integrase inhibitors. Dolutegravir. ATC code J05AJ03.

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).

Pharmacokinetics.

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

Food intake increased the extent and slowed the rate of dolutegravir absorption. The bioavailability of dolutegravir depends on the composition of food: low-, medium-, and high-fat meals increased the 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 2 hours under fasting conditions. This increase in pharmacokinetic parameters may be clinically significant in patients with existing resistance to integrase inhibitor class drugs. Therefore, the drug is 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, according to population pharmacokinetic analysis. Total blood-to-plasma ratios of radioactivity associated with the drug range 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 detected in cerebrospinal fluid (CSF). In 13 treatment-naïve patients who were receiving dolutegravir in combination with abacavir/lamivudine during the study, the concentration of dolutegravir in CSF averaged 18 ng/mL (which is at the level of the unbound fraction concentration in plasma and above IC50).

Dolutegravir is detected in the genital tract of both 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 lesser extent by CYP3A. Dolutegravir circulates predominantly 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 biliary excretion of the glucuronide conjugate, which may subsequently break down to form 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 a metabolite formed by oxidation at the benzyl carbon (3% of total dose).

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

Clinical characteristics.

Indications.

The medicinal product is indicated in combination with other antiretroviral agents for the treatment of adults, adolescents, and children aged 12 years and older who are infected with human immunodeficiency virus (HIV).

Contraindications.

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

Concomitant use with medicinal products that have a narrow therapeutic window and are substrates of organic cation transporter 2 (OCT2), including 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, factors that reduce dolutegravir concentrations must be avoided.

Dolutegravir is primarily eliminated via metabolism mediated by the UGT1A1 enzyme. Dolutegravir is also a substrate of UGT1A3, U游戏副本1A9, 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 below). Concomitant administration of dolutegravir with other medicinal products that inhibit these enzymes may increase dolutegravir plasma concentrations (see Table 1).

The absorption of dolutegravir is reduced by certain antacids (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, in patients, a 10–14% reduction in creatinine clearance has been observed (the secretory component depends 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 effect of tenofovir substrate on OAT pharmacokinetics in vivo, in vivo inhibition of OAT1 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 denoted 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

Drug classes	Interaction, geometric mean change (%)	Recommendations for co-administration
Antiviral drugs against HIV-1
Non-nucleoside reverse transcriptase inhibitors
Etravirine (without boosted protease inhibitors)	Dolutegravir ↓ AUC ↓ 71% Cmax ↓ 52% Cτ ↓ 88% Etravirine ↔ (induction of UGT1A1 and CYP3A enzymes)	Etravirine without boosted protease inhibitors reduces dolutegravir plasma concentrations. The recommended dose of dolutegravir is 50 mg twice daily when administered with etravirine without boosted protease inhibitors. For children, the weight-based daily dose should be divided into two administrations. Dolutegravir should not be used with etravirine without concomitant administration of atazanavir/ritonavir, darunavir/ritonavir, or lopinavir/ritonavir in patients with resistance to integrase inhibitors (see below in the table).
Lopinavir/ ritonavir + etravirine	Dolutegravir ↔ AUC ↑ 11% Cmax ↑ 7% Cτ ↑ 28% Lopinavir ↔ Ritonavir ↔	No dose adjustment required.
Darunavir/ ritonavir + etravirine	Dolutegravir ↓ AUC ↓ 25% Cmax ↓ 12% Cτ ↓ 36% Darunavir ↔ Ritonavir ↔	No dose adjustment required.
Efavirenz	Dolutegravir ↓ AUC ↓ 57% Cmax ↓ 39% Cτ ↓ 75% Efavirenz ↔ (historical controls) (induction of UGT1A1 and CYP3A enzymes)	The recommended dose of dolutegravir is 50 mg twice daily when co-administered with efavirenz. For children, the weight-based daily dose should be divided into two administrations. Alternative combinations not including efavirenz should be considered in case of resistance to integrase inhibitors.
Nevaripine	Dolutegravir ↓ (not studied, similar reduction expected due to induction as observed with efavirenz)	The recommended dose of dolutegravir is 50 mg twice daily when co-administered with nevirapine. Alternative combinations not including nevirapine should be considered in case of resistance to integrase inhibitors.
Rilpivirine	Dolutegravir ↔ AUC ↑ 12% Cmax ↑ 13% Cτ ↑ 22% Rilpivirine ↔	No dose adjustment required.
Nucleoside reverse transcriptase inhibitors
Tenofovir	Dolutegravir ↔ AUC ↑ 1% Cmax ↓ 3% Cτ ↓ 8% Tenofovir ↔	No dose adjustment required.
Protease inhibitors
Atazanavir	Dolutegravir ↑ AUC ↑ 91% Cmax ↑ 50% Cτ ↑ 180% Atazanavir ↔ (historical controls) (inhibition of UGT1A1 and CYP3A enzymes)	No dose adjustment required. Dolutegravir should not be administered at doses higher than 50 mg twice daily in combination with atazanavir due to lack of data.
Atazanavir/ ritonavir	Dolutegravir ↑ AUC ↑ 62% Cmax ↑ 34% Cτ ↑ 121% Atazanavir ↔ Ritonavir ↔ (inhibition of UGT1A1 and CYP3A enzymes)	No dose adjustment required. Dolutegravir should not be administered at doses higher than 50 mg twice daily in combination with atazanavir due to lack of data.
Tipranavir/ ritonavir	Dolutegravir ↓ AUC ↓ 59% Cmax ↓ 47% Cτ ↓ 76% (induction of UGT1A1 and CYP3A enzymes)	The recommended dose of dolutegravir is 50 mg twice daily when co-administered with tipranavir/ritonavir in the absence of resistance to integrase inhibitors. For children, the weight-based daily dose should be divided into two administrations. This combination should be avoided if resistance to integrase inhibitors is present.
Fosamprenavir/ ritonavir	Dolutegravir ↓ AUC ↓ 35% Cmax ↓ 24% Cτ ↓ 49% (induction of UGT1A1 and CYP3A enzymes)	No dose adjustment required in the absence of resistance to integrase inhibitors. Alternative combinations not including fosamprenavir/ritonavir should be considered if resistance to integrase inhibitors is present.
Darunavir/ ritonavir	Dolutegravir ↓ AUC ↓ 22% Cmax ↓ 11% C24 ↓ 38% (induction of UGT1A1 and CYP3A enzymes)	No dose adjustment required.
Lopinavir/ ritonavir	Dolutegravir ↔ AUC ↓ 4% Cmax ↔ 0% C24 ↓ 6%	No dose adjustment required.
Other antiviral drugs
Daclatasvir	Dolutegravir ↔ AUC ↑ 33% Cmax ↑ 29% Cτ ↑ 45% Daclatasvir ↔	Daclatasvir does not significantly alter dolutegravir plasma concentrations. Dolutegravir does not alter daclatasvir plasma concentrations. No dose adjustment required.
Other drugs
Anticonvulsants
Carbamazepine	Dolutegravir ↓ AUC ↓ 49% Cmax ↓ 33% Cτ ↓ 73%	The recommended dose of dolutegravir for adults is 50 mg twice daily when co-administered with carbamazepine. For children, the weight-based daily dose should be divided into two administrations. Alternative agents to carbamazepine should be considered, if possible, in patients with resistance to integrase inhibitors.
Oxcarbazepine Phenytoin Phenobarbital	Dolutegravir ↓ (not studied, reduction expected due to induction of UGT1A1 and CYP3A enzymes; exposure reduction similar to that observed with carbamazepine is expected)	The recommended dose of dolutegravir is 50 mg twice daily when co-administered with these enzyme inducers. For children, the weight-based daily dose should be divided into two administrations. Alternative combinations to these enzyme inducers should be considered, if possible, in patients with resistance to integrase inhibitors.
Potassium channel blockers
Fampridine (also known as dalfampridine)	Fampridine ↑	Co-administration of dolutegravir may cause seizures due to increased plasma concentrations of fampridine via inhibition of the OCT2 transporter. Co-administration has not been studied and is contraindicated.
Azole antifungal agents
Ketoconazole Fluconazole Itraconazole Posaconazole Voriconazole	Dolutegravir ↔ (not studied)	No dose adjustment required. Based on data from other CYP3A4 inhibitors, a significant increase is not expected.
Herbal products
St. John’s wort	Dolutegravir ↓ (not studied, reduction expected due to induction of UGT1A1 and CYP3A enzymes; exposure reduction similar to that observed with carbamazepine is expected)	The recommended dose of dolutegravir is 50 mg twice daily when co-administered with St. John’s wort. For children, the weight-based daily dose should be divided into two administrations. Alternative combinations not including St. John’s wort should be considered, if possible, in patients with resistance to integrase inhibitors.
Antacids and dietary supplements
Antacids containing magnesium/aluminum	Dolutegravir ↓ AUC ↓ 74% Cmax ↓ 72% (chelation with polyvalent ions)	Antacids containing magnesium/aluminum should be taken separately from dolutegravir (at least 2 hours after or 6 hours before dolutegravir administration).
Calcium-containing supplements	Dolutegravir ↓ AUC ↓ 39% Cmax ↓ 37% C24 ↓ 39% (chelation with polyvalent ions)	Calcium, iron supplements, or multivitamins should be taken separately from dolutegravir (at least 2 hours after or 6 hours before dolutegravir administration).
Iron-containing supplements	Dolutegravir ↓ AUC ↓ 54% Cmax ↓ 57% C24 ↓ 56% (chelation with polyvalent ions)
Multivitamins	Dolutegravir ↓ AUC ↓ 33% Cmax ↓ 35% C24 ↓ 32% (chelation with polyvalent ions)
Corticosteroids
Prednisone	Dolutegravir ↔ AUC ↑ 11% Cmax ↑ 6% Cτ ↑ 17%	No dose adjustment required.
Antidiabetic agents
Metformin	Metformin ↑ With co-administration of dolutegravir 50 mg once daily: Metformin: AUC ↑ 79% Cmax ↑ 66% With co-administration of dolutegravir 50 mg twice daily: Metformin: AUC ↑ 145% Cmax ↑ 111%	Dose adjustment of metformin should be considered at the initiation and upon discontinuation of concomitant dolutegravir to maintain glycemic control. For patients with moderate renal impairment, metformin dose adjustment should be considered when co-administered with dolutegravir, as increased metformin concentrations may increase the risk of lactic acidosis in these patients (see section "Special warnings and precautions for use").
Antituberculosis agents
Rifampicin	Dolutegravir ↓ AUC ↓ 54% Cmax ↓ 43% Cτ ↓ 72% (induction of UGT1A1 and CYP3A enzymes)	The recommended dose of dolutegravir is 50 mg twice daily when co-administered with rifampicin in the absence of resistance to integrase inhibitors. For children, the weight-based daily dose should be divided into two administrations. This combination should be avoided if resistance to integrase inhibitors is present (see section "Special warnings and precautions for use").
Rifabutin	Dolutegravir ↔ AUC ↓ 5% Cmax ↑ 16% Cτ ↓ 30% (induction of UGT1A1 and CYP3A enzymes)	No dose adjustment required.
Oral contraceptives
Ethinylestradiol and norelgestromin	Dolutegravir ↔ Ethinylestradiol ↔ AUC ↑ 3% Cmax ↓ 1% Norelgestromin ↔ AUC ↓ 2% Cmax ↓ 11%	Dolutegravir has no pharmacodynamic effect on luteinizing hormone (LH), follicle-stimulating hormone (FSH), or progesterone. No dose adjustment of oral contraceptives is required when co-administered with dolutegravir.
Analgesics
Methadone	Dolutegravir ↔ Methadone ↔ AUC ↓ 2% Cmax ↔ 0% Cτ ↓ 1%	No dose adjustment required for either drug.

Children.

Interaction studies have been conducted only in adults.

Special precautions for use.

Although effective suppression of the virus with antiretroviral agents 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 current recommendations.

Resistance to integrase inhibitor class drugs of particular concern.

When considering the use of dolutegravir in the presence of resistance to integrase inhibitor class drugs, it should be noted that the 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. It is unclear whether dolutegravir provides additional efficacy in the presence of such resistance to integrase inhibitors.

Hypersensitivity reactions.

Hypersensitivity reactions, characterized by rash, systemic symptoms, and sometimes organ dysfunction, including severe hepatic reactions, have been reported with dolutegravir. Dolutegravir and other drugs that may cause hypersensitivity reactions should be discontinued immediately if signs or symptoms of hypersensitivity occur (including severe rash or rash accompanied by elevated liver enzymes, fever, malaise, fatigue, muscle or joint pain, blistering, oral lesions, conjunctivitis, facial swelling, eosinophilia, or angioedema). Clinical status should be monitored, including assessment of hepatic aminotransferases and bilirubin levels. Delay in discontinuing dolutegravir or other potentially causative agents may lead to a life-threatening allergic reaction.

Immune Reconstitution Syndrome.

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

In some patients co-infected with hepatitis B and/or C virus, increased biochemical markers of liver function have been observed at the start of treatment with dolutegravir.

Monitoring of liver function tests is recommended in patients co-infected with hepatitis B and/or C virus. Particular caution is required at the initiation and during maintenance of effective hepatitis B therapy (according to treatment guidelines) when starting dolutegravir-based therapy 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 must be avoided. These include concomitant use of medicinal products that reduce dolutegravir concentrations (such as antacids containing magnesium/aluminum, 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 the initiation and discontinuation of concomitant dolutegravir and metformin therapy to maintain glycemic control (see section "Interaction with other medicinal products and other forms of interaction"). Metformin is eliminated by the kidneys, so renal function should be monitored during concomitant therapy with dolutegravir. The combination of these agents increases the risk of lactic acidosis in patients with moderate renal impairment (stage 3a, creatinine clearance [CrCl] 45–59 mL/min); therefore, special attention is recommended. The physician should consider reducing the metformin dose.

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 their physician if they experience joint pain, stiffness, or difficulty in movement.

Weight and metabolic parameters.

Weight gain and increases in blood lipid and glucose levels may occur during antiretroviral therapy. These changes may be partly associated with disease control and lifestyle. Regarding lipids, there is some evidence of a treatment effect in certain cases, whereas for weight gain, there is no strong evidence linking it to any specific therapy. Management of lipid and glucose levels should follow current HIV treatment guidelines. Lipid abnormalities should be managed according to clinical need.

Lamivudine and dolutegravir.

The two-component regimen of dolutegravir 50 mg once daily and lamivudine 300 mg once daily was evaluated in two large randomized, blinded trials, GEMINI 1 and GEMINI 2. This regimen is indicated only for the treatment of HIV-1 infection in the absence of known or suspected resistance to integrase inhibitors or lamivudine.

Precautions regarding excipients.

Film-coated tablets contain mannitol, which may have a mild laxative effect.

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

Use during pregnancy or breastfeeding.

Fertile women.

Fertile women should be counselled about the potential risk of neural tube defects (see below) prior to initiating 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 3591 births (0.19%; 95% CI 0.09%, 0.40%) in women who received a dolutegravir-containing regimen from conception, compared to 21 cases among 19,361 births (0.11%; 95% CI 0.07%, 0.17%) in women who received a regimen without dolutegravir from conception.

In the same study, two newborns (0.04%) among 4448 births whose mothers received dolutegravir during pregnancy had neural tube defects, compared to five cases among 6748 births (0.07%) in women who received a regimen without dolutegravir.

The background incidence of neural tube defects in the general population is 0.5–1 case per 1000 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 planned or confirmed during the first trimester while on dolutegravir, 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 for neural tube defect development.

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

In animal reproductive toxicity studies, dolutegravir showed no adverse effects on fetal development, including neural tube defects. Dolutegravir crosses the placenta in animals.

More than 1000 outcomes from dolutegravir exposure in women during the second and third trimesters of pregnancy indicate no increased risk of fetal/neonatal toxicity. Dolutegravir may be used during the second and third trimesters of pregnancy only if the expected benefit to the woman outweighs the potential risk to the fetus.

Breastfeeding.

Dolutegravir is excreted in human breast milk in small amounts.

Information on the effects of dolutegravir on neonates/infants is limited.

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

Fertility.

Data on the effect of dolutegravir on fertility in men and women are lacking. Animal studies did not show any effect of dolutegravir on fertility in males or females.

Ability to drive and use machines.

Studies on the effects 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 considered when determining the ability to drive or operate machinery.

Method of Administration and Dosage.

The medicinal product should be prescribed by a physician experienced in the management of HIV infection.

Dosage.

Adult patients infected with HIV-1, without documented or clinically suspected resistance to integrase inhibitors.

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

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

Adult patients infected with HIV-1, with resistance to integrase inhibitors (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 G140A/C/S, E138A/K/T, L74I, modeling predicts that dose escalation may be beneficial for patients with limited treatment options (fewer than 2 active agents) due to developed multiclass resistance. When considering the use of dolutegravir in such patients, resistance to integrase inhibitors should be taken into account.

Missed dose.

If a patient misses a dose of the medicinal product, they should take it as soon as possible, provided that the next dose is not due within the next 4 hours. If the next dose is due within the next 4 hours, the patient should not take the missed dose and should return to their regular dosing schedule.

Children aged 12 years and older.

For children (aged 12 to 17 years, with body weight at least 40 kg) infected with HIV-1 and 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 for adolescents with resistance to integrase inhibitors.

Elderly patients.

The amount of data available on the use of dolutegravir in patients aged 65 years and older is limited. There is no evidence that elderly patients require a different dosage compared to younger adult patients.

Renal impairment.

No dose adjustment is necessary for patients with mild, moderate, or severe renal impairment (creatinine clearance [CrCl] < 30 mL/min, not on dialysis). Data in patients on dialysis are lacking, although 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 such patients.

Method of administration.

Oral administration.

The medicinal product can be taken with or without food.

If resistance to integrase inhibitors is present, the medicinal product should be taken with food to increase its effect (particularly in patients with Q148 mutations).

Children.

The medicinal product is administered to children aged 12 years and older. Safety and efficacy of dolutegravir in children under 12 years of age or with body weight less than 40 kg have not been established. If resistance to integrase inhibitors exists, there are insufficient data to recommend the use of the medicinal product in children and adolescents.

Overdose.

To date, experience with dolutegravir overdose is limited.

Based on limited experience with single high doses (up to 250 mg in healthy volunteers), no additional specific symptoms or signs were observed beyond those listed as adverse reactions. There is no specific antidote for dolutegravir overdose. In case 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 serious adverse reaction observed in individual patients was hypersensitivity reaction, including rash and severe hepatic effects (see section "Special warnings and precautions for use"). The most commonly 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 class 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

Body systems	Frequency	Adverse reactions
Immune system disorders	Uncommon	Hypersensitivity, immune reconstitution syndrome (see "Special precautions")*
Psychiatric disorders	Common	Insomnia, abnormal dreams, depression, anxiety
Psychiatric disorders	Uncommon	Suicidal thoughts, suicide attempts (particularly in patients with a history of depression or psychiatric illness), panic attacks
Nervous system disorders	Very common	Headache
Nervous system disorders	Common	Dizziness
Gastrointestinal disorders	Very common	Nausea, diarrhea
Gastrointestinal disorders	Common	Vomiting, flatulence, upper abdominal pain, abdominal pain, abdominal discomfort
Hepatobiliary disorders	Uncommon Rare	Hepatitis Acute liver failure, increased bilirubin levels**
Skin and subcutaneous tissue disorders	Common	Rash, pruritus
General disorders and administration site conditions	Common	Fatigue
Abnormal laboratory or other test results	Common	Elevated creatine phosphokinase (CPK) levels
Musculoskeletal and connective tissue disorders	Uncommon	Arthralgia Myalgia

* See below in the section "Description of selected adverse reactions".

**In combination with increased transaminase levels.

Description of selected 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

Patients with concurrent hepatitis B and/or C virus infection were allowed in phase III studies provided baseline liver function biochemical parameters did not exceed five times the upper limit of normal. 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 (aspartate aminotransferase) and ALT (alanine aminotransferase) levels 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 start of dolutegravir treatment, particularly in those who discontinued hepatitis B treatment (see section "Special precautions").

Immune Reconstitution Syndrome

In HIV-infected patients with severe 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 disease is more variable, and these events may occur many months after initiation of treatment (see section "Special precautions").

Metabolic parameters

During antiretroviral therapy, a patient's weight and blood lipid and glucose levels may increase.

Children

According to available data, in children aged 12 years and older with body weight of at least 40 kg, no additional types of adverse reactions have been reported beyond those identified in adults.

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

Shelf life.

2 years.

Storage conditions.

Store at temperatures not exceeding 30 °C in the original packaging.

Keep out of reach of children.

Packaging.

30 tablets in a bottle, 1 bottle in a cardboard package;

30 tablets in a bottle.

Prescription status.

Prescription only.

Manufacturer.

Macleods Pharmaceuticals Limited, India

Manufacturer's address and location of operation.

Phase II, Plot No. 12, 15, 21, 23, 24, 25, 26, 27, 28 and 30, Survey No. 366, Premier Industrial Estate, Kachigam, Daman, 396210, India

Dolutegravir 50 mg