Myltega

Dolutegravir.

Each film-coated tablet contains 52.6mg dolutegravir sodium equivalent to 50mg dolutegravir.
Excipients/Inactive Ingredients: Core tablet: mannitol, povidone, sodium starch glycolate, microcrystalline cellulose and sodium stearyl fumarate.
Film coating (Opadry II brown 85F565142): polyvinyl alcohol, macrogol/polyethylene glycol, talc, titanium dioxide, red iron oxide and black iron oxide.

Pharmacotherapeutic group: Antivirals for systemic use, other antivirals. ATC code: J05AJ03.
Pharmacology: Pharmacodynamics: Mechanism of action: Dolutegravir inhibits HIV integrase by binding to the integrase active site and blocking the strand transfer step of retroviral Deoxyribonucleic acid (DNA) integration which is essential for the HIV replication cycle.
Pharmacodynamic effects: Antiviral activity in cell culture: The IC₅₀ for dolutegravir in various labstrains using PBMC was 0.5 nM, and when using MT-4 cells it ranged from 0.7-2 nM. Similar IC_50s were seen for clinical isolates without any major difference between subtypes; in a panel of 24 HIV-1 isolates of clades A, B, C, D, E, F and G and group O the mean IC₅₀ value was 0.2 nM (range 0.02-2.14). The mean IC₅₀ for 3 HIV-2 isolates was 0.18 nM (range 0.09-0.61).
Antiviral activity in combination with other antiviral agents: No antagonistic effects were seen with dolutegravir and other antiretrovirals tested: stavudine, abacavir, efavirenz, nevirapine, lopinavir, amprenavir, enfuvirtide, maraviroc and raltegravir. In addition, no antagonistic effects were seen for dolutegravir and adefovir, and ribavirin had no apparent effect on dolutegravir activity.
Effect of human serum: In 100% human serum, the mean protein fold shift was 75 fold, resulting in protein adjusted IC90 of 0.064 µg/mL.
Resistance: Mutations selected appeared slowly using the lab-strain HIV-1 IIIB during passage, with substitutions at positions S153Y and F, resulting in a maximal fold change in susceptibility of 4.
Mutation R263K was reported from ART experienced, INI naive individual patients with subtypes B and C, but without effects on dolutegravir susceptibility. G118R lowers the susceptibility to dolutegravir in site directed mutants (FC 10), but was not detected in patients receiving dolutegravir.
Primary mutations for raltegravir/elvitegravir (Q148H/R/K, N155H, Y143R/H/C, E92Q and T66I) do not affect the susceptibility of dolutegravir as single mutations. When mutations listed as secondary integrase inhibitor associated mutations (for raltegravir/elvitegravir) are added to these primary mutations with site directed mutants, dolutegravir susceptibility is still unchanged (FC <2 vs wild type virus), except in the case of Q148-mutations, where a FC of 5-10 or higher is seen with combinations of certain secondary mutations. With strain NL432, starting with site directed mutants harbouring N155H or E92Q, no further selection of resistance was seen (FC unchanged around 1). In contrast, starting with mutants harbouring mutation Q148H (FC 1), a variety of secondary mutations were seen with a consequent increase of FC to values >10.
A clinically relevant phenotypic cut-off value (FC vs wild type virus) has not been determined; genotypic resistance was a better predictor for outcome.
Dolutegravir has a less than or equal to 10 FC against 94% of isolates from raltegravir experienced patients.
Resistance: In previously untreated patients receiving dolutegravir + 2 NRTIs, no development of resistance to the integrase class, or to the NRTI class was seen. In previously untreated patients receiving dolutegravir + lamivudine through week 96, no development of resistance to the integrase class, or to the NRTI class was seen.
In patients with prior failed therapies, but naïve to the integrase class, integrase inhibitor substitutions were observed in patients treated with dolutegravir, which was given in combination with an selected background regimen (BR).
In the presence of integrase class-resistance, treatment emergent integrase resistance typically appeared in patients with a history of the Q148-mutation (baseline or historic). Treatment-emergent mutations or mixtures of mutations observed were L74I, N155H.
In paediatric patients with prior failed therapies, but naïve to the integrase class, the integrase inhibitor substitution G118R was observed in patients treated with dolutegravir, given in combination with an selected background regimen. Dolutegravir FC (fold change as compared to wildtype virus) ranged from 6 to 25-fold.
Effects on electrocardiogram: No relevant effects were seen on the QTc interval, with doses exceeding the clinical dose by approximately three fold.
Pharmacokinetics: Dolutegravir pharmacokinetics are similar between healthy and HIV-infected patients. The PK variability of dolutegravir is low to moderate. Between-patient CVb% for AUC and C_max ranged from ~20 to 40% and C_τ from 30 to 65%. The between-patient PK variability of dolutegravir was higher in HIV-infected patients than healthy patients. Within-patient variability (CVw%) is lower than between-patient variability.
Film-coated tablets and dispersible tablets do not have the same bioavailability. The relative bioavailability of dispersible tablets is approximately 1.6-fold higher as compared to film-coated tablets. Thus, a 50 mg dolutegravir dose administered as film-coated tablet(s) will have similar exposure to a 30 mg dolutegravir dose administered as six 5 mg dispersible tablets. Similarly, a 40 mg dolutegravir dose administered as four 10 mg film-coated tablets will provide comparable exposure to a 25 mg dolutegravir dose administered as five 5 mg dispersible tablets.
Absorption: Dolutegravir is rapidly absorbed following oral administration, with median T_max at 2 to 3 hours post dose for tablet formulation.
Food increased the extent and slowed the rate of absorption of dolutegravir. Bioavailability of dolutegravir depends on meal content: low, moderate, and high fat meals increased dolutegravir AUC_(0-∞) by 33%, 41%, and 66%, increased C_max by 46%, 52%, and 67%, prolonged T_max to 3, 4, and 5 hours from 2 hours under fasted conditions, respectively for the film-coated tablet. These increases may be clinically relevant in the presence of certain integrase class resistance. Therefore, MYLTEGA is recommended to be taken with food by patients infected with HIV with integrase class resistance (see Dosage & Administration).
The absolute bioavailability of dolutegravir has not been established.
Distribution: Dolutegravir is highly bound (>99%) to human plasma proteins based on data. The apparent volume of distribution is 17 L to 20 L in HIV-infected patients. Binding of dolutegravir to plasma proteins is independent of dolutegravir concentration. Total blood and plasma drug-related radioactivity concentration ratios averaged between 0.441 to 0.535, indicating minimal association of radioactivity with blood cellular components. The unbound fraction of dolutegravir in plasma is increased at low levels of serum albumin (<35 g/L) as seen in patients with moderate hepatic impairment.
Dolutegravir is present in cerebrospinal fluid (CSF). In treatment-naïve patients on a stable dolutegravir plus abacavir/lamivudine regimen, dolutegravir concentration in CSF averaged 18 ng/mL (comparable to unbound plasma concentration, and above the IC₅₀).
Dolutegravir is present in the female and male genital tract. AUC in cervicovaginal fluid, cervical tissue and vaginal tissue were 6-10% of those in corresponding plasma at steady state. AUC in semen was 7% and 17% in rectal tissue of those in corresponding plasma at steady state.
Biotransformation: Dolutegravir is primarily metabolized through glucuronidation via UGT1A1 with a minor CYP3A component. Dolutegravir is the predominant circulating compound in plasma; renal elimination of unchanged active substance is low (< 1% of the dose). Fifty-three percent of total oral dose is excreted unchanged in the faeces. It is unknown if all or part of this is due to unabsorbed active substance or biliary excretion of the glucuronidate conjugate, which can be further degraded to form the parent compound in the gut lumen. Thirty-two percent of the total oral dose is excreted in the urine, represented by ether glucuronide of dolutegravir (18.9% of total dose), N-dealkylation metabolite (3.6% of total dose), and a metabolite formed by oxidation at the benzylic carbon (3.0% of total dose).
Drug interactions: Dolutegravir demonstrated no direct, or weak inhibition (IC₅₀>50 μM) of the enzymes cytochrome _P450 (CYP)1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 CYP3A, uridine diphosphate glucuronosyl transferase (UGT)1A1 or UGT2B7, or the transporters Pgp, BCRP, BSEP, OATP1B1, OATP1B3, OCT1, MATE2-K, MRP2 or MRP4. Dolutegravir did not induce CYP1A2, CYP2B6 or CYP3A4. Based on this data, dolutegravir is not expected to affect the pharmacokinetics of medicinal products that are substrates of major enzymes or transporters (see Interactions).
Dolutegravir was not a substrate of human OATP 1B1, OATP 1B3 or OCT 1.
Elimination: Dolutegravir has a terminal half-life of ~14 hours. The apparent oral clearance (CL/F) is approximately 1L/hr in HIV-infected patients based on a population pharmacokinetic analysis.
Linearity/non-linearity: The linearity of dolutegravir pharmacokinetics is dependent on dose and formulation. Following oral administration of film-coated tablet formulations, in general, dolutegravir exhibited nonlinear pharmacokinetics with less than dose-proportional increases in plasma exposure from 2 to 100 mg; however increase in dolutegravir exposure appears dose proportional from 25 mg to 50 mg for the film-coated tablet formulation. With 50 mg film-coated tablet twice daily, the exposure over 24 hours was approximately doubled compared to 50 mg film-coated tablet once daily.
Pharmacokinetic/pharmacodynamic relationship(s): In HIV-1-infected patients treated with dolutegravir monotherapy (ING111521), it demonstrated rapid and dose-dependent antiviral activity, with mean decline in HIV-1 RNA of 2.5 log₁₀ at day 11 for 50 mg dose. This antiviral response was maintained for 3 to 4 days after the last dose in the 50 mg film-coated tablet group.
PK/PD modelling in integrase resistant patients suggest that increasing the dose from 50 mg film-coated tablet twice daily to 100 mg film-coated tablet twice daily may increase the effectiveness of dolutegravir in patients with integrase resistance and limited treatment options due to advanced multi class resistance. The proportion of responders (HIV-1 RNA <50 c/mL) at week 24 was predicted to increase around 4-18% in the patients with Q148 + ≥2 secondary mutations from G140A/C/S, E138A/K/T, L74I. This high dose may be considered in the presence of the Q148 + ≥2 secondary mutations from G140A/C/S, E138A/K/T, L74I in patients with overall limited treatment options due to advanced multi class resistance. There is no clinical data on the safety or efficacy of the 100 mg film-coated tablet twice daily dose. Co-treatment with atazanavir increases the exposure of dolutegravir markedly, and should not be used in combination with this high dose, since safety with the resulting dolutegravir exposure has not been established.
Special patient populations: Children: Steady state simulated plasma exposure at once daily weight band doses n HIV-1 infected infants, children and adolescents aged ≥ 4 weeks to < 18 years is summarized in Table 1. (See Table 1.)

Click on icon to see table/diagram/image

Steady state simulated plasma exposure at alternative twice daily weight band doses are summarized in Table 2. (See Table 2.)

Click on icon to see table/diagram/image

Elderly: In HIV-1 infected adults showed that there was no clinically relevant effect of age on dolutegravir exposure.
Pharmacokinetic data for dolutegravir in patients >65 years of age are limited.
Renal impairment: Renal clearance of unchanged active substance is a minor pathway of elimination for dolutegravir. The exposure to dolutegravir was decreased by approximately 40% in patients with severe renal impairment. The mechanism for the decrease is unknown. No dosage adjustment is considered necessary for patients with renal impairment. There is no data of use of Dolutegravir in patients on dialysis.
Hepatic impairment: Dolutegravir is primarily metabolized and eliminated by the liver. While the total dolutegravir concentration in plasma was similar, a 1.5- to 2-fold increase in unbound exposure to dolutegravir was observed in patients with moderate hepatic impairment compared to healthy patients. No dosage adjustment is considered necessary for patients with mild to moderate hepatic impairment. There is no data on effect of severe hepatic impairment on the pharmacokinetics of Doluteragravir.
Polymorphisms in drug metabolising enzymes: There is no evidence that common polymorphisms in drug metabolising enzymes alter dolutegravir pharmacokinetics to a clinically meaningful extent. Patients with UGT1A1 genotypes conferring poor dolutegravir metabolism had a 32% lower clearance of dolutegravir and 46% higher AUC via UGT1A1.
Gender: There is no clinically relevant effect of gender on the exposure of dolutegravir.
Race: There is no clinically relevant effect of race on the exposure of dolutegravir. The pharmacokinetics of dolutegravir following single dose oral administration to Japanese patients appear similar to observed parameters in Western (US) patients.
Co-infection with Hepatitis B or C: Population pharmacokinetic analysis indicated that hepatitis C virus co-infection had no clinically relevant effect on the exposure to dolutegravir. There are limited data on patients with hepatitis B co-infection.

MYLTEGA is indicated in combination with other anti-retroviral medicinal products for the treatment of Human Immunodeficiency Virus (HIV) infected adults and adolescents above 12 years of age.

MYLTEGA should be prescribed by physicians experienced in the management of HIV infection.
Posology: Adults: Patients infected with HIV-1 without documented or clinically suspected resistance to the integrase class: The recommended dose of dolutegravir is 50 mg (one tablet) orally once daily.
MYLTEGA should be administered twice daily in this population when co-administered with some medicines (e.g. efavirenz, nevirapine, tipranavir/ritonavir, or rifampicin). Refer to Interactions.
Patients infected with HIV-1 with resistance to the integrase class (documented or clinically suspected): The recommended dose of dolutegravir is 50 mg (one tablet) twice daily.
In the presence of documented resistance that includes Q148 + ≥ 2 secondary mutations from G140A/C/S, E138A/K/T, L74I, modelling suggests that an increased dose may be considered for patients with limited treatment options (less than 2 active agents) due to advanced multi class resistance (see Pharmacology: Pharmacokinetics under Actions).
The decision to use dolutegravir for such patients should be informed by the integrase resistance pattern (see Pharmacology: Pharmacodynamics under Actions).
Adolescents aged 12 and above: In adolescents (12 to less than 18 years of age and weighing at least 40 kg) infected with HIV-1 without resistance to the integrase class, the recommended dose of dolutegravir is 50 mg once daily. In the presence of integrase inhibitor resistance, there are insufficient data to recommend a dose for dolutegravir in adolescents.
Missed doses: If the patient misses a dose of MYLTEGA, the patient should take MYLTEGA as soon as possible, providing the next dose is not due within 4 hours. If the next dose is due within 4 hours, the patient should not take the missed dose and simply resume the usual dosing schedule.
Elderly: There are limited data available on the use of dolutegravir in patients aged 65 years and over. There is no evidence that elderly patients require a different dose than younger adult patients (see Pharmacology: Pharmacokinetics under Actions).
Renal impairment: No dosage adjustment is required in patients with mild, moderate or severe (CrCl <30 mL/min, not on dialysis) renal impairment. Limited data are available in patients receiving dialysis, although differences in pharmacokinetics are not expected in this population (see Pharmacology: Pharmacokinetics under Actions).
Hepatic impairment: No dosage adjustment is required in patients with mild or moderate hepatic impairment (Child-Pugh grade A or B). No data are available in patients with severe hepatic impairment (Child-Pugh grade C); therefore dolutegravir should be used with caution in these patients (see Pharmacology: Pharmacokinetics under Actions).
Paediatric population: The safety and efficacy of MYLTEGA in children aged less than 12 years or weighing less than 40 kg has not yet been established. In the presence of integrase inhibitor resistance, there are insufficient data to recommend a dose for MYLTEGA in children and adolescents. Currently available data are described in Adverse Reactions, Pharmacology: Pharmacodynamics and Pharmacokinetics under Actions, but no recommendation on a posology can be made.
Method of administration: Oral use.
MYLTEGA can be taken with or without food (see Pharmacology: Pharmacokinetics under Actions). In the presence of integrase class resistance, MYLTEGA should preferably be taken with food to enhance exposure (particularly in patients with Q148 mutations) (see Pharmacology: Pharmacokinetics under Actions).

There is currently limited experience with overdosage in dolutegravir.
Limited experience of single higher doses (up to 250 mg) revealed no specific symptoms or signs, apart from those listed as adverse reactions.
Further management should be as clinically indicated or as recommended by the national poisons centre, where available. There is no specific treatment for an overdose of dolutegravir. If overdose occurs, the patient should be treated supportively with appropriate monitoring, as necessary. As dolutegravir is highly bound to plasma proteins, it is unlikely that it will be significantly removed by dialysis.

Hypersensitivity to the active substance or to any of the excipients listed under Description.
Medicinal products with narrow therapeutic windows that are substrates of organic cation transporter 2 (OCT2), including but not limited to fampridine (also known as dalfampridine; see Interactions).

While effective viral suppression with antiretroviral therapy has been proven to substantially reduce the risk of sexual transmission, a residual risk cannot be excluded. Precautions to prevent transmission should be taken in accordance with national guidelines.
Integrase class resistance of particular concern: The decision to use dolutegravir in the presence of integrase class resistance should take into account that the activity of dolutegravir is considerably compromised for viral strains harbouring Q148+≥2 secondary mutations from G140A/C/S, E138A/K/T, L74I (see Pharmacology: Pharmacodynamics under Actions). To what extent dolutegravir provides added efficacy in the presence of such integrase class resistance is uncertain (see Pharmacology: Pharmacokinetics under Actions).
Hypersensitivity reactions: Hypersensitivity reactions have been reported with dolutegravir, and were characterized by rash, constitutional findings, and sometimes, organ dysfunction, including severe liver reactions. Dolutegravir and other suspect medicinal products should be discontinued immediately if signs or symptoms of hypersensitivity reactions develop (including, but not limited to, severe rash or rash accompanied by raised liver enzymes, fever, general malaise, fatigue, muscle or joint aches, blisters, oral lesions, conjunctivitis, facial oedema, eosinophilia, angioedema). Clinical status including liver aminotransferases and bilirubin should be monitored. Delay in stopping treatment with dolutegravir or other suspect active substances after the onset of hypersensitivity may result in a life-threatening allergic reaction.
Immune Reactivation Syndrome: In HIV-infected patients with severe immune deficiency at the time of institution of combination antiretroviral therapy (CART), an inflammatory reaction to asymptomatic or residual opportunistic pathogens may arise and cause serious clinical conditions, or aggravation of symptoms. Typically, such reactions have been observed within the first few weeks or months of initiation of CART. Relevant examples are cytomegalovirus retinitis, generalised and/or focal mycobacterial infections, and Pneumocystis jirovecii pneumonia. Any inflammatory symptoms should be evaluated and treatment instituted when necessary. Autoimmune disorders (such as Graves' disease and autoimmune hepatitis) have also been reported to occur in the setting of immune reconstitution, however, the reported time to onset is more variable and these events can occur many months after initiation of treatment.
Liver biochemistry elevations consistent with immune reconstitution syndrome were observed in some hepatitis B and/or C co-infected patients at the start of dolutegravir therapy. Monitoring of liver biochemistries is recommended in patients with hepatitis B and/or C co-infection. Particular diligence should be applied in initiating or maintaining effective hepatitis B therapy (referring to treatment guidelines) when starting dolutegravir-based therapy in hepatitis B co-infected patients (see Adverse Reactions).
Opportunistic infections: Patients should be advised that dolutegravir or any other antiretroviral therapy 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 observation by physicians experienced in the treatment of these associated HIV diseases.
Drug interactions: Factors that decrease dolutegravir exposure should be avoided in the presence of integrase class resistance. This includes co-administration with medicinal products that reduce dolutegravir exposure (e.g. magnesium/aluminium-containing antacid, iron and calcium supplements, multivitamins and inducing agents, etravirine (without boosted protease inhibitors), tipranavir/ritonavir, rifampicin, St. John's wort and certain anti-epileptic medicinal products) (see Interactions).
Dolutegravir increased metformin concentrations. A dose adjustment of metformin should be considered when starting and stopping coadministration of dolutegravir with metformin, to maintain glycaemic control (see Interactions). Metformin is eliminated renally and, therefore, it is of importance to monitor renal function when co-treated with dolutegravir. This combination may increase the risk for lactic acidosis in patients with moderate renal impairment (stage 3a creatinine clearance [CrCl] 45-59 mL/min) and a cautious approach is recommended. Reduction of the metformin dose should be highly considered.
Osteonecrosis: Although the aetiology is considered to be multifactorial (including corticosteroid use, biphosphonates, alcohol consumption, severe immunosuppression, higher body mass index), cases of osteonecrosis have been reported in patients with advanced HIV-disease and/or long-term exposure to CART. Patients should be advised to seek medical advice if they experience joint aches and pain, joint stiffness or difficulty in movement.
Weight and metabolic parameters: An increase in weight and in levels of blood lipids and glucose may occur during antiretroviral therapy. Such changes may in part be linked to disease control and lifestyle. For lipids, there is in some cases evidence for a treatment effect, while for weight gain there is no strong evidence relating this to any particular treatment.
For monitoring of blood lipids and glucose reference is made to established HIV treatment guidelines. Lipid disorders should be managed as clinically appropriate.
Lamivudine and dolutegravir: This two-drug regimen of dolutegravir 50 mg once daily and lamivudine 300 mg once daily is only suitable for the treatment of HIV-1 infection where there is no known or suspected resistance to the integrase inhibitor class, or to lamivudine.
Effects on ability to drive and use machines: Patients should be informed that dizziness has been reported during treatment with dolutegravir. The clinical status of the patient and the adverse reaction profile of dolutegravir should be borne in mind when considering the patient's ability to drive or operate machinery.

Women of childbearing potential: Women of childbearing potential (WOCBP) should be counselled about the potential risk of neural tube defects with dolutegravir (see as follows), including consideration of effective contraceptive measures.
If a woman plans pregnancy, the benefits and the risks of continuing treatment with dolutegravir should be discussed with the patient.
Pregnancy: There is a small increase of neural tube defects to mothers taking dolutegravir-containing regimens at the time of conception.
The incidence of neural tube defects in the general population ranges from 0.5-1 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 a pregnancy is confirmed in the first trimester while on dolutegravir, the benefits and risks of continuing dolutegravir versus switching to another antiretroviral regimen should be discussed with the patient taking the gestational age and the critical time period of neural tube defect development into account.
Data analysed do not indicate an increased risk of major birth defects in women exposed to dolutegravir during pregnancy but are currently insufficient to address the risk of neural tube defects.
No adverse development outcomes, including neural tube defects, were identified. Dolutegravir was shown to cross the placenta in animals.
More than 1000 outcomes from exposure during second and third trimester of pregnancy indicate no evidence of increased risk of foeto/neonatal toxicity. Dolutegravir may be used during the second and third trimester of pregnancy when the expected benefit justifies the potential risk to the foetus.
Breast-feeding: Dolutegravir is excreted in human milk in small amounts. There is insufficient information on the effects of dolutegravir in neonates/infants.
It is recommended that HIV infected women do not breast-feed their infants under any circumstances in order to avoid transmission of HIV.
Fertility: There are no data on the effects of dolutegravir on human male or female fertility. Animal data indicate no effects of dolutegravir on male or female fertility.

Summary of the safety profile: The most severe adverse reaction, seen in an individual patient, was a hypersensitivity reaction that included rash and severe liver effects (see Precautions). The most commonly seen treatment emergent adverse reactions were nausea, diarrhoea and headache.
Tabulated list of adverse reactions: The adverse reactions considered at least possibly related to dolutegravir are listed by body system, organ class and absolute frequency. Frequencies are defined as very common, common, uncommon, rare, very rare. (See Table 3.)

Click on icon to see table/diagram/image

Description of selected adverse reactions: Changes in laboratory biochemistries: Increases in serum creatinine occurred within the first week of treatment with dolutegravir and remained stable through 48 weeks. A mean change from baseline of 9.96 μmol/L was observed after 48 weeks of treatment.
Creatinine increases were comparable by various background regimens. These changes are not considered to be clinically relevant since they do not reflect a change in glomerular filtration rate.
Co-infection with Hepatitis B or C: Overall, the safety profile in patients co-infected with hepatitis B and/or C was similar to that observed in patients without hepatitis B or C co-infection, although the rates of AST and ALT abnormalities were higher in the subgroup with hepatitis B and/or C co-infection for all treatment groups. Liver chemistry elevations consistent with immune reconstitution syndrome were observed in some patients with hepatitis B and/or C co-infection at the start of dolutegravir therapy, particularly in those whose anti-hepatitis B therapy was withdrawn (see Precautions).
Immune reactivation syndrome: In HIV-infected patients with severe immune deficiency at the time of initiation of combination antiretroviral therapy (CART), an inflammatory reaction to asymptomatic or residual opportunistic infections may arise. Autoimmune disorders (such as Graves' disease and autoimmune hepatitis) have also been reported; however, the reported time to onset is more variable and these events can occur many months after initiation of treatment (see Precautions).
Metabolic parameters: Weight and levels of blood lipids and glucose may increase during antiretroviral therapy (see Precautions).
Paediatric population: Based on available data, children and adolescents (aged 4 weeks and above, to less than 18 years, and weighing at least 3 kg) who received the recommended doses of film-coated tablets or dispersible tablets once daily, there were no additional types of adverse reactions beyond those observed in the adult population.

Effect of other agents on the pharmacokinetics of dolutegravir: All factors that decrease dolutegravir exposure should be avoided in the presence of integrase class resistance.
Dolutegravir is eliminated mainly through metabolism by UGT1A1. Dolutegravir is also a substrate of UGT1A3, UGT1A9, CYP3A4, Pgp, and BCRP; therefore medicinal products that induce those enzymes may decrease dolutegravir plasma concentration and reduce the therapeutic effect of dolutegravir (see Table 4).
Co-administration of dolutegravir and other medicinal products that inhibit these enzymes may increase dolutegravir plasma concentration (see Table 4).
The absorption of dolutegravir is reduced by certain anti-acid agents (see Table 4).
Effect of dolutegravir on the pharmacokinetics of other agents: Dolutegravir did not have an effect on midazolam, a CYP3A4 probe. Dolutegravir is not expected to affect the pharmacokinetics of medicinal products that are substrates of any major enzyme or transporter such as CYP3A4, CYP2C9 and P-gp (for more information see Pharmacology: Pharmacokinetics under Actions).
Dolutegravir inhibited the renal organic cation transporter 2 (OCT2) and multidrug and toxin extrusion transporter (MATE) 1. A 10-14% decrease of creatinine clearance (secretory fraction is dependent on OCT2 and MATE-1 transport) was observed. Dolutegravir may increase plasma concentrations of medicinal products in which excretion is dependent upon OCT2 and/or MATE-1 (e.g. fampridine [also known as dalfampridine], metformin) (see Table 4).
Dolutegravir inhibited the renal uptake transporters, organic anion transporters (OAT1) and OAT3. Based on the lack of effect on the pharmacokinetics of the OAT substrate tenofovir, inhibition of OAT1 is unlikely. There is no data on inhibition of OAT3. Dolutegravir may increase plasma concentrations of medicinal products in which excretion is dependent upon OAT3.
Established and theoretical interactions with selected antiretrovirals and non-antiretroviral medicinal products are listed in Table 4.
Interaction table: Interactions between dolutegravir and co-administered medicinal products are listed in Table 4 (increase is indicated as "↑", decrease as "↓", no change as "↔", area under the concentration versus time curve as "AUC", maximum observed concentration as "Cmax", concentration at end of dosing interval as "C^τ"). (See Table 4.)

Click on icon to see table/diagram/image


Click on icon to see table/diagram/image


Click on icon to see table/diagram/image

Paediatric population: Interaction data have only been performed in adults.

Incompatibilities: Not applicable.
Instruction for use, handling and disposal: No special requirements.
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

Do not store above 30°C. Store in the original container.
Shelf life: 36 months.

Antivirals

J05AJ03 - dolutegravir ; Belongs to the class of integrase inhibitors. Used as direct acting antiviral in the systemic treatment of viral infections.

B