DOVATO 50 MG / 300 MG FILM-COATED TABLETS - summary of medicine characteristics

Dovato 50 mg/300 mg film-coated tablets

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each film-coated tablet contains dolutegravir sodium equivalent to 50 mg dolutegravir and 300 mg lamivudine.

For the full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Film-coated tablet (tablet).

Oval, biconvex, white, film coated tablet, approximately 18.5 × 9.5 mm, debossed with “SV 137” on one face.

4.1 Therapeutic indications

Dovato is indicated for the treatment of Human Immunodeficiency Virus type 1 (HIV-1) infection in adults and adolescents above 12 years of age weighing at least 40 kg, with no known or suspected resistance to the integrase inhibitor class, or lamivudine (see section 5.1).

4.2 Posology and method of administration

Dovato should be prescribed by physicians experienced in the management of HIV infection.

Posology

Adults and adolescents (above 12 years of age weighing at least 40 kg).

The recommended dose of Dovato in adults and adolescents is one 50 mg/300 mg tablet once daily.

Dose adjustments

A separate preparation of dolutegravir is available where a dose adjustment is indicated due to drug-drug interactions (e.g. rifampicin, carbamazepine, oxcarbazepine, phenytoin, phenobarbital, St. John’s wort, etravirine (without boosted protease inhibitors), efavirenz, nevirapine, or tipranavir/ri­tonavir, see sections 4.4 and 4.5). In these cases the physician should refer to the individual product information for dolutegravir.

Missed doses

If the patient misses a dose of Dovato, the patient should take Dovato 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 Dovato in patients aged 65 years and over. No dose adjustment is necessary (see section 5.2).

Renal impairment

Dovato is not recommended for use in patients with a creatinine clearance < 50 mL/min (see section 5.2). No dose adjustment is required in patients with mild renal impairment.

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 Dovato should be used with caution in these patients (see section 5.2).

Paediatric population

The safety and efficacy of Dovato in children aged less than 12 years or weighing less than 40 kg have not been established. No data are available.

Method of administration

Oral use.

Dovato can be taken with or without food (see section 5.2).

4.3 Contraindications

Hypersensitivity to the active substances or to any of the excipients listed in section 6.1.

Co-administration with medicinal products with narrow therapeutic windows, that are substrates of organic cation transporter (OCT) 2, including but not limited to fampridine (also known as dalfampridine; see section 4.5).

4.4 Special warnings and precautions for use

Transmission of HIV

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.

Hypersensitivity reactions

Hypersensitivity reactions have been reported with dolutegravir, and were characterized by rash, constitutional findings, and sometimes, organ dysfunction, including severe liver reactions. Dovato 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 Dovato or other suspect active substances after the onset of hypersensitivity may result in a life-threatening allergic reaction.

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 life style. 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.

Liver disease

Patients with chronic hepatitis B or C and treated with combination antiretroviral therapy are at an increased risk of severe and potentially fatal hepatic adverse reactions. In case of concomitant antiviral therapy for hepatitis B or C, please refer also to the relevant product information for these medicinal products.

Dovato includes lamivudine, which is active against hepatitis B. Dolutegravir lacks such activity. Lamivudine monotherapy is generally not considered an adequate treatment for hepatitis B, since the risk for hepatitis B resistance development is high. If Dovato is used in patients co-infected with hepatitis B an additional antiviral is therefore generally needed. Reference should be made to treatment guidelines.

If Dovato is discontinued in patients co-infected with hepatitis B virus, periodic monitoring of both liver function tests and markers of HBV replication is recommended, as withdrawal of lamivudine may result in an acute exacerbation of hepatitis.

Patients with pre-existing liver dysfunction, including chronic active hepatitis have an increased frequency of liver function abnormalities during combination antiretroviral therapy, and should be monitored according to standard practice. If there is evidence of worsening liver disease in such patients, interruption or discontinuation of treatment must be considered.

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 (often referred to as PCP). 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 reactivation; however, the reported time to onset is more variable and these events can occur many months after initiation of treatment.

Liver chemistry 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 chemistries is recommended in patients with hepatitis B and/or C co-infection. (See ‘Liver disease’ earlier in this section and also see section 4.8).

Mitochondrial dysfunction following exposure in utero

Nucleoside and nucleotide analogues may impact mitochondrial function to a variable degree, which is most pronounced with stavudine, didanosine and zidovudine. There have been reports of mitochondrial dysfunction in HIVnegative infants exposed in utero and/or post-natally to nucleoside analogues, these have predominantly concerned treatment with regimens containing zidovudine. The main adverse reactions reported are haematological disorders (anaemia, neutropenia), and metabolic disorders (hyperlactatemia, hyperlipasemia). These reactions have often been transitory. Some late-onset neurological disorders have been reported rarely (hypertonia, convulsion, abnormal behaviour). Whether such neurological disorders are transient or permanent is currently unknown. These findings should be considered for any child exposed in utero to nucleoside and nucleotide analogues, who presents with severe clinical findings of unknown aetiology, particularly neurologic findings. These findings do not affect current national recommendations to use antiretroviral therapy in pregnant women to prevent vertical transmission of HIV.

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.

Opportunistic infections

Patients should be advised that dolutegravir, lamivudine 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

The recommended dose of dolutegravir is 50 mg twice daily when coadministered with rifampicin, carbamazepine, oxcarbazepine, phenytoin, phenobarbital, St. John’s wort, etravirine (without boosted protease inhibitors), efavirenz, nevirapine, or tipranavir/ri­tonavir (see section 4.5).

Dovato should not be co-administered with polyvalent cation-containing antacids. Polyvalent cation-containing antacids are recommended to be taken 2 hours after or 6 hours before Dovato (see section 4.5).

When taken with food, Dovato and supplements or multivitamins containing calcium, iron or magnesium can be taken at the same time. If Dovato is administered under fasting conditions, supplements or multivitamins containing calcium, iron or magnesium are recommended to be taken 2 hours after or 6 hours before Dovato (see section 4.5).

Dolutegravir increased metformin concentrations. A dose adjustment of metformin should be considered when starting and stopping coadministration of Dovato with metformin, to maintain glycaemic control (see section 4.5). Metformin is eliminated renally and, therefore, it is of importance to monitor renal function when co-treated with Dovato. This combination may increase the risk for lactic acidosis in patients with moderate renal impairment (stage 3a creatinine clearance 45– 59 mL/min) and a cautious approach is recommended. Reduction of the metformin dose should be highly considered.

The combination of Dovato with cladribine is not recommended (see section 4.5).

Dovato should not be taken with any other medicinal product containing dolutegravir, lamivudine or emtricitabine, except where a dose adjustment of dolutegravir is indicated due to drug-drug interactions (see section 4.5).

4.5 Interaction with other medicinal products and other forms of interaction

No drug interaction studies have been conducted using Dovato. Dovato contains dolutegravir and lamivudine, therefore any interactions identified for these individually are relevant to Dovato. No clinically significant drug interactions are expected between dolutegravir and lamivudine.

Effect of other medicinal products on the pharmacokinetics of dolutegravir and lamivudine

Dolutegravir is eliminated mainly through metabolism by uridine diphosphate glucuronosyl transferase (UGT) 1A1. Dolutegravir is also a substrate of UGT1A3, UGT1A9, CYP3A4, P-glycoprotein (P-gp), and breast cancer resistance protein (BCRP). Co-administration of Dovato and other medicinal products that inhibit UGT1A1, UGT1A3, UGT1A9, CYP3A4, and/or P-gp may, therefore, increase dolutegravir plasma concentration. Medicinal products that induce those enzymes or transporters may decrease dolutegravir plasma concentration and reduce the therapeutic effect of dolutegravir.

The absorption of dolutegravir is reduced by certain metal cation-containing anti-acid substances and supplements (see Table 1).

Lamivudine is cleared renally. Active renal secretion of lamivudine in the urine is mediated through the OCT2 and multidrug and toxin extrusion transporters (MATE1 and MATE2-K). Trimethoprim (an inhibitor of these transporters) has been shown to increase lamivudine plasma concentrations, however the resulting increase was not clinically significant (see Table 1). Dolutegravir is an OCT2 and MATE1 inhibitor; however, lamivudine concentrations were similar with or without co-administration of dolutegravir

based on a cross study analysis, indicating that dolutegravir has no relevant effect on lamivudine exposure in vivo. Lamivudine is also substrate of the hepatic uptake transporter OCT1. As hepatic elimination plays a minor role in the clearance of lamivudine, drug interactions due to inhibition of OCT1 are unlikely to be of clinical significance.

Although lamivudine is a substrate of BCRP and P-gp in vitro, given its high absolute bioavailability, (see section 5.2), inhibitors of these efflux transporters are unlikely to result in a clinically relevant impact on lamivudine concentrations.

Effect of dolutegravir and lamivudine on the pharmacokinetics of other medicinal products

In vivo, dolutegravir did not have an effect on midazolam, a CYP3A4 probe. Based on in vivo and/or in vitro data, 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 section 5.2).

In vitro, dolutegravir inhibited the renal transporters OCT2 and MATE1. In vivo, a 10–14% decrease of creatinine clearance (secretory fraction is dependent on OCT2 and MATE1 transport) was observed in patients. In vivo, dolutegravir may increase plasma concentrations of medicinal products in which excretion is dependent upon OCT2 and/or MATE1 (e.g. fampridine [also known as dalfampridine], metformin) (see Table 1 and section 4.3).

In vitro, dolutegravir inhibited the renal uptake organic anion transporters (OAT)1 and OAT3. Based on the lack of effect on the in vivo pharmacokinetics of the OAT substrate tenofovir, in vivo inhibition of OAT1 is unlikely. Inhibition of OAT3 has not been studied in vivo. Dolutegravir may increase plasma concentrations of medicinal products in which excretion is dependent upon OAT3.

In vitro, lamivudine was an inhibitor of OCT1 and OCT2; the clinical consequences are not known.

Established and theoretical interactions with selected antiretrovirals and nonantiretroviral medicinal products are listed in Table 1.

Interaction table

Interactions between dolutegravir, lamivudine and co-administered medical products are listed in Table 1 (increase is indicated as “f”, 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 “Ct”). The table should not be considered exhaustive but is representative of the classes studied.

Table 1:     Drug Interactions

Paediatric population

Interaction studies have only been performed in adults.

4.6 Fertility, pregnancy and lactation

Women of childbearing potential

Women of childbearing potential (WOCBP) should be counselled about the potential risk of neural tube defects with dolutegravir (a component of Dovato, see below), including consideration of effective contraceptive measures.

If a woman plans pregnancy, the benefits and the risks of continuing treatment with Dovato should be discussed with the patient.

Pregnancy

The safety and efficacy of a dual regimen has not been studied in pregnancy.

Human experience from a birth outcome surveillance study in Botswana shows a small increase of neural tube defects; 7 cases in 3,591 deliveries (0.19%; 95% CI 0.09%, 0.40%) to mothers taking dolutegravir-containing regimens at the time of conception compared to 21 cases in 19,361 deliveries (0.11%: 95% CI 0.07%, 0.17%) to women exposed to non-dolutegravir regimens at the time of conception.

The incidence of neural tube defects in the general population ranges from 0.51 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 Dovato, the benefits and risks of continuing Dovato 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 from the Antiretroviral Pregnancy Registry do not indicate an increased risk of major birth defects in over 600 women exposed to dolutegravir during pregnancy but are currently insufficient to address the risk of neural tube defects.

In animal reproductive toxicology studies with dolutegravir, no adverse development outcomes, including neural tube defects, were identified (see section 5.3). Dolutegravir was shown to cross the placenta in animals.

More than 1000 outcomes from exposure to dolutegravir during second and third trimester pregnancy indicate no evidence of increased risk of foeto/neonatal toxicity. Dovato may be used during the second and third trimester of pregnancy when the expected benefit justifies the potential risk to the foetus.

A large amount of data on the use of lamivudine in pregnant women (more than 5200 outcomes from first trimester) indicates no malformative toxicity.

Animal studies showed lamivudine may inhibit cellular DNA replication (see section 5.3). The clinical relevance of these findings is unknown.

Mitochondrial dysfunction

Nucleoside and nucleotide analogues have been demonstrated in vitro and in vivo to cause a variable degree of mitochondrial damage. There have been reports of mitochondrial dysfunction in HIV-negative infants exposed in utero and/or post-natally to nucleoside analogues (see section 4.4).

Breast-feeding

Dolutegravir is excreted in human milk in small amounts. There is insufficient information on the effects of dolutegravir in neonates/infants.

Based on more than 200 mother/child pairs treated for HIV, serum concentrations of lamivudine in breastfed infants of mothers treated for HIV are very low (< 4% of maternal serum concentrations) and progressively decrease to undetectable levels when breastfed infants reach 24 weeks of age. There are no data available on the safety of lamivudine when administered to babies less than three months old.

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 or lamivudine on human male or female fertility. Animal studies indicate no effects of dolutegravir or lamivudine on male or female fertility (see section 5.3).

4.7 Effects on ability to drive and use machines

Dovato has no or negligible influence on the ability to drive and use machines. Patients should be informed that dizziness and somnolence has been reported during treatment with dolutegravir. The clinical status of the patient and the adverse reaction profile of Dovato should be borne in mind when considering the patient’s ability to drive or operate machinery.

4.8 Undesirable effects

Summary of the safety profile

The most frequently reported adverse reactions are headache (3%), diarrhoea (2%), nausea (2%) and insomnia (2%).

The most severe adverse reaction reported with dolutegravir was a hypersensitivity reaction that included rash and severe liver effects (see section 4.4).

Tabulated list of adverse reactions

The adverse reactions from clinical study and post-marketing experience are listed in Table 2 by body system, organ class and absolute frequency. Frequencies are defined as very common (>1/10), common (>1/100 to <1/10), uncommon (>1/1,000 to <1/100), rare (>1/10,000 to <1/1,000), very rare (<1/10,000), not known (cannot be estimated from the available data).

Table 2:     Tabulated summary of adverse reactions to Dovato based on

clinical study and post-marketing experience with Dovato and its individual components__________­________________________­______

2 In combination with increased transaminases.

Description of selected adverse reactions

Changes in laboratory biochemistries

Dolutegravir has been associated with an increase in serum creatinine occuring in the first week of treatment when administered with other antiretroviral medicinal products. Increases in serum creatinine occurred within the first four weeks of treatment with dolutegravir plus lamivudine and remained stable through 48 weeks. In the pooled GEMINI studies a mean change from baseline of 10.3 |imol/L (range: –36.3 |imol/L to 55.7 |imol/L) was observed after 48 weeks of treatment. These changes are linked to the inhibiting effect of dolutegravir on renal tubular transporters of creatinine. The changes are not considered to be clinically relevant and do not reflect a change in glomerular filtration rate.

Co-infection with Hepatitis B or C

In the Phase III studies for the dolutegravir single agent, patients with hepatitis B and/or C co-infection were permitted to enrol provided that baseline liver chemistry tests did not exceed 5 times the upper limit of normal (ULN). 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 subjects with hepatitis B and/or C coinfection at the start of dolutegravir therapy, particularly in those whose anti-hepatitis B therapy was withdrawn (see section 4.4).

Metabolic parameters

Weight and levels of blood lipids and glucose may increase during antiretroviral therapy (see section 4.4).

Osteonecrosis

Cases of osteonecrosis have been reported, particularly in patients with generally acknowledged risk factors, advanced HIV disease or long-term exposure to CART. The frequency of this is unknown (see section 4.4).

Immune response 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 section 4.4).

Paediatric population

There are no clinical study data on the effects of Dovato in the paediatric population.

Individual components have been investigated in adolescents (12 to 17 years).

Based on limited available data with the dolutegravir single entity or lamivudine single entity used in combination with other antiretroviral agents to treat adolescents (12 to 17 years), there were no additional types of adverse reactions beyond those observed in the adult population.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via Yellow Card Scheme Website:

http://www.mhra­.gov.uk/yellow­card or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9 Overdose

No specific symptoms or signs have been identified following acute overdose with dolutegravir or lamivudine, apart from those listed as adverse reactions.

There is no specific treatment for an overdose of Dovato. If overdose occurs, the patient should be treated supportively with appropriate monitoring, as necessary. Since lamivudine is dialysable, continuous haemodialysis could be used in the treatment of overdose, although this has not been studied. As dolutegravir is highly bound to plasma proteins, it is unlikely that it will be significantly removed by dialysis.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Antivirals for systemic use, antivirals for treatment of HIV infections, combinations. ATC code: J05AR25

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.

Lamivudine, via its active metabolite 5'-triphosphates (TP) (an analogue for cytidine), inhibits reverse transcriptase of HIV-1 and HIV-2 through incorporation of the monophosphate form into the viral DNA chain, resulting in chain termination. Lamivudine triphosphate shows significantly less affinity for host cell DNA polymerases.

Pharmacodynamic effects

Antiviral activity in cell culture

Dolutegravir and lamivudine have been shown to inhibit replication of lab-strains and clinical isolates of HIV in a number of cell types, including transformed T cell lines, monocyte/macrophage derived lines and primary cultures of activated peripheral blood mononuclear cells (PMBCs) and monocyte/macrop­hages. The concentration of active substance necessary to effect viral replication by 50% (IC50 – half maximal inhibitory concentration) varied according to virus and host cell type.

The IC50 for dolutegravir in various lab-strains using PBMC was 0.5 nM, and when using MT-4 cells it ranged from 0.7–2 nM. Similar IC50s 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).

The median or mean IC50 values for lamivudine against lab-strains of HIV-1 ranged from 0.007 to 2.3 pM. The mean IC50 against lab-strains of HIV-2 (LAV2 and EHO) ranged from 0.16 to 0.51 pM for lamivudine. The IC50 values of lamivudine against HIV-1 subtypes (A-G) ranged from 0.001 to 0.170 pM, against Group O from 0.030 to 0.160 pM and against HIV-2 isolates from 0.002 to 0.120 pM in peripheral blood mononuclear cells.

HIV-1 isolates (CRF01_AE, n=12; CRF02_AG, n=12; and Subtype C or CRF_AC, n=13) from 37 untreated patients in Africa and Asia were susceptible to lamivudine (IC50 fold changes < 3.0). Group O isolates from antiviral naïve patients tested for lamivudine activity were highly sensitive.

Effect of human serum

In 100% human serum, the mean fold shift for dolutegravir activity was 75 fold, resulting in protein adjusted IC90 of 0.064 pg/mL. Lamivudine exhibits linear pharmacokinetics over the therapeutic dose range and displays low plasma protein binding (less than 36%).

Resistance

Dovato is indicated in the absence of documented or suspected resistance to the integrase inhibitor class and to lamivudine (see section 4.1). For information around in vitro resistance, and cross resistance to other agents of the integrase- and NRTI class, please refer to the SmPCs of dolutegravir and lamivudine.

None of the twelve subjects in the dolutegravir plus lamivudine group or the nine subjects in the dolutegravir plus tenofovir disoproxil/em­tricitabine FDC group that met virological withdrawal criteria through Week 144 across the GEMINI-1 (204861) and GEMINI-2 (205543) studies had treatment emergent integrase inhibitor or NRTI class resistance.

In previously untreated patients receiving dolutegravir + 2 NRTIs in Phase IIb and Phase III, no development of resistance to the integrase inhibitor class, or to the NRTI class was seen (n=1118 follow-up of 48–96 weeks).

Effects on electrocardiogram

No relevant effects were seen with dolutegravir on the QTc interval, with doses exceeding the clinical dose by approximately three fold. A similar study was not conducted with lamivudine.

Clinical efficacy and safety

Antiretroviral naïve subjects

The efficacy of Dovato is supported by data from 2 identical 148-week, Phase III, randomised, double-blind, multicentre, parallel-group, non-inferiority controlled trials GEMINI-1 (204861) and GEMINI-2 (205543). A total of 1433 HIV-1 infected antiretroviral treatment-naïve adult subjects received treatment in the trials. Subjects were enrolled with a screening plasma HIV-1 RNA of 1000 c/mL to <500,000 c/mL. Subjects were randomised to a two-drug regimen of dolutegravir 50 mg plus lamivudine 300 mg once daily or dolutegravir 50 mg plus tenofovir disoproxil/em­tricitabine 245/200 mg once daily. The primary efficacy endpoint for each GEMINI trial was the proportion of subjects with plasma HIV-1 RNA <50 copies/mL at Week 48 (Snapshot algorithm for the ITT-E population). Double blind therapy will continue up to week 96, followed by open label therapy up to week 148.

At baseline, in the pooled analysis, the median age of subjects was 33 years, 15% were female, 69% were white, 9% were CDC Stage 3 (AIDS), 20% had HIV-1 RNA >100,000 copies/mL, and 8% had CD4+ cell count less than 200 cells per mm3; these characteristics were similar between studies and treatment arms.

In the primary week 48 analysis, dolutegravir plus lamivudine was non-inferior to dolutegravir plus tenofovir disoproxil/em­tricitabine FDC in GEMINI-1 and GEMINI-2 studies. This was supported by the pooled analysis, see Table 3.

Table 3 Virologic Outcomes of Randomised Treatment of GEMINI at

Week 48 (Snapshot algorithm)

* The results of the pooled analysis are in line with those of the individual studies, for which the primary endpoint (difference in proportion <50 copies/mL plasma HIV-1 RNA at Week 48 based on the Snapshot algorithm for dolutegravir plus lamivudine versus dolutegravir plus tenofovir disoproxil /emtricitabine FDC) was met. The adjusted difference was –2.6 (95% CI: –6.7; 1.5) for GEMINI-1 and –0.7 (95% CI: –4.3; 2.9) for GEMINI-2 with a prespecified non-inferiority margin of 10%.

f Based on CMH-stratified analysis adjusting for the following baseline stratification factors: Plasma HIV-1 RNA (<100,000 c/mL vs. >100,000 c/mL) and CD4+ cell count (<200 cells/mm3 vs. >200 cells/mm3). Pooled analysis also stratified by study. Assessed using a non-inferiority margin of 10%.

N = Number of subjects in each treatment group

At 96 weeks and at 144 weeks in the GEMINI studies, the lower bound of the 95% confidence interval for the adjusted treatment difference of proportion of subjects with HIV-1 RNA <50 copies/mL (Snapshot) was greater than the non-inferiority margin of –10%, for the individual studies as well as pooled analysis, see Table 4.

Table 4 Virologic Outcomes of Randomised Treatment of GEMINI at

Weeks 96 and 144 (Snapshot algorithm)

* The results of the pooled analysis are in line with those of the individual studies.

f Based on CMH-stratified analysis adjusting for the following baseline stratification factors: Plasma HIV-1 RNA (<100,000 c/mL vs. >100,000 c/mL) and CD4+ cell count (<200 cells/mm3 vs. >200 cells/mm3). Pooled analysis also stratified by study.

Assessed using a non-inferiority margin of 10%.

N = Number of subjects in each treatment group

The mean increase in CD4+ T-cell counts through week 144 was 302 cells/mm3 in the dolutegravir plus lamivudine arm and 300 cells/mm3 in the dolutegravir plus tenofovir/emtri­citabine arm.

Virologically suppressed subjects

The efficacy of dolutegravir/la­mivudine in virologically suppressed subjects is supported by data from a randomised, open-label, trial (TANGO [204862]). A total of 741 adult HIV-1 infected subjects, without any evidence of resistance to the NRTI or integrase inhibitor (INSTI) class and who were on a stable suppressive tenofovir alafenamide based regimen (TBR) received treatment in the studies. Subjects were randomised in a 1:1 ratio to receive dolutegravir/la­mivudine FDC or continue with TBR for up to 200 weeks. Randomisation was stratified by baseline core agent class (protease inhibitor [PI], INSTI, or non-nucleoside reverse transcriptase inhibitor [NNRTI]). The primary efficacy endpoint was the proportion of subjects with plasma HIV-1 RNA >50 c/mL (virologic non-response) as per the FDA Snapshot category at Week 48 (adjusted for randomisation stratification factor).

At baseline the median age of subjects was 39 years, 8% were female and 21% nonwhite, 5% were CDC Class C (AIDS) and 98% subjects had Baseline CD4+ cell count >200 cells/mm3; these characteristics were similar between treatment arms. Subjects had been on ART for a median of around 3 years prior to Day 1 Around 80% were on INSTI-based TBR (mainly elvitegravir/c) at baseline.

In the primary 48 week analysis dolutegravir/la­mivudine was non-inferior to TBR, with <1% of subjects in both arms experiencing virologic failure (HIV-1 RNA >50 c/mL)(Table 5).

Table 5 Virologic Outcomes of Randomised Treatment of TANGO at

Week 48 (Snapshot algorithm)

in the secondary analysis (proportion of subjects achieving <50 copies/mL plasma HIV-1 RNA).

Based on a 4% non-inferiority margin, DTG/3TC is non-inferior to TBR at Week 48 in the primary analysis (proportion of subjects with plasma HIV-1 RNA >50 c/mL). fBased on CMH-stratified analysis adjusting for Baseline third agent class (PI, NNRTI, INSTI).

N = Number of subjects in each treatment group; TBR = tenofovir alafenamide based regimen.

Treatment outcomes between treatment arms at week 48 were similar across the stratification factor, baseline third agent class and across subgroups by age, sex, race, baseline CD4+ cell count, CDC HIV disease stage, and countries. The median change from baseline in CD4+ count at Week 48 was 22.5 cells per mm3 in subjects who switched to dolutegravir/la­mivudine and 11.0 cells per mm3 in subjects who stayed on TBR.

At 96 weeks in the TANGO study, the proportion of subjects with HIV-1 RNA >50 c/mL (Snapshot) was 0.3% and 1.1% in the dolutegravir/la­mivudine and TBR groups, respectively. Based on a non-inferiority margin of 4%, dolutegravir/la­mivudine remained non-inferior to TBR, as the upper bound of the 95% CI for the adjusted treatment difference (-2.0%; 0.4%) was less than 4% for the ITT E Population.

The median change from baseline in CD4+ T-cell counts at week 96 was 61 cells/mm3 in the dolutegravir/la­mivudine arm and 45 cells/mm3 in the TBR arm.

Paediatric population

The efficacy of Dovato, or the dual combination of dolutegravir plus lamivudine (as single entities) has not been studied in children or adolescents.

The European Medicines Agency has deferred the obligation to submit the results of studies with Dovato in one or more subsets of the paediatric population in the treatment of HIV infection.

Table 4 Virologic Outcomes of Randomised Treatment of TANGO at

Week 48 (Snapshot algorithm)

in the secondary analysis (proportion of subjects achieving <50 copies/mL plasma HIV-1 RNA).

Based on a 4% non-inferiority margin, DTG/3TC is non-inferior to TBR at Week 48 in the primary analysis (proportion of subjects with plasma HIV-1 RNA >50 c/mL). fBased on CMH-stratified analysis adjusting for Baseline third agent class (PI, NNRTI, INSTI).

N = Number of subjects in each treatment group; TBR = tenofovir alafenamide based regimen.

Treatment outcomes between treatment arms at week 48 were similar across the stratification factor, baseline third agent class and across subgroups by age, sex, race, baseline CD4+ cell count, CDC HIV disease stage, and countries. The median change from baseline in CD4+ count at Week 48 was 22.5 cells per mm3 in subjects who switched to dolutegravir/la­mivudine and 11.0 cells per mm3 in subjects who stayed on TBR.

At 96 weeks in the TANGO study, the proportion of subjects with HIV-1 RNA >50 c/mL (Snapshot) was 0.3% and 1.1% in the dolutegravir/la­mivudine and TBR groups, respectively. Based on a non-inferiority margin of 4%, dolutegravir/la­mivudine remained non-inferior to TBR, as the upper bound of the 95% CI for the adjusted treatment difference (-2.0%; 0.4%) was less than 4% for the ITT E Population.

The median change from baseline in CD4+ T-cell counts at week 96 was 61 cells/mm3 in the dolutegravir/la­mivudine arm and 45 cells/mm3 in the TBR arm.

Paediatric population

The efficacy of Dovato, or the dual combination of dolutegravir plus lamivudine (as single entities) has not been studied in children or adolescents.

The European Medicines Agency has deferred the obligation to submit the results of studies with Dovato in one or more subsets of the paediatric population in the treatment of HIV infection.

5.2 Pharmacokinetic properties

When administered in fasted state, bioequivalence regarding Cmax was achieved for dolutegravir, when comparing Dovato to dolutegravir 50 mg coadministered with lamivudine 300 mg. Dolutegravir AUC0-t was 16% higher for Dovato than for dolutegravir 50 mg co-administered with lamivudine 300 mg. This increase is not considered clinically relevant.

When administered in fasted state, bioequivalence was achieved for lamivudine AUC, when comparing Dovato to lamivudine 300 mg coadministered with dolutegravir 50 mg. Lamivudine Cmax for Dovato was 32% higher than lamivudine 300 mg co-administered with dolutegravir 50 mg. The higher lamivudine Cmax, is not considered clinically relevant.

Absorption

Dolutegravir and lamivudine are rapidly absorbed following oral administration. The absolute bioavailability of dolutegravir has not been established. The absolute bioavailability of oral lamivudine in adults is approximately 80–85%. For Dovato, the median time to maximal plasma concentration (tmax) is 2.5 hours for dolutegravir and 1.0 hour for lamivudine, when dosed under fasted conditions.

Exposure to dolutegravir was generally similar between healthy subjects and HIV-1-infected subjects. In HIV-1-infected adult subjects following dolutegravir 50 mg once daily, the steady-state pharmacokinetic parameters (geometric mean [%CV]) based on population pharmacokinetic analyses were AUC(0–24) = 53.6 (27) ^g.h/mL, Cmax = 3.67 (20) Llg ml., and Cmin = 1.11 (46) Llg/ml.. Following multiple-dose oral administration of lamivudine 300 mg once daily for seven days, the mean (CV) steady-state Cmax is 2.04 |ig/mL (26%) and the mean (CV) AUC(0–24) is 8.87 gg.h/mL (21%).

Administration of a single Dovato tablet with a high fat meal increased dolutegravir AUC(0.~) and Cmax by 33% and 21%, respectively, and decreased the lamivudine Cmax by 30% compared to fasted conditions. The lamivudine AUC(0_~) was not affected by a high fat meal. These changes are not clinically significant. Dovato may be administered with or without food.

Distribution

The apparent volume of distribution of dolutegravir (Vd/F) is 17–20 L. Intravenous studies with lamivudine showed that the mean apparent volume of distribution is 1.3 L/kg.

Dolutegravir is highly bound (> 99%) to human plasma proteins based on in vitro data. 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 subjects with moderate hepatic impairment. Lamivudine exhibits linear pharmacokinetics over the therapeutic dose range and displays limited plasma protein binding in vitro (< 16%- 36% to serum albumin).

Dolutegravir and lamivudine are present in cerebrospinal fluid (CSF). In 13 treatment-naive subjects 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). The mean ratio of CSF/serum lamivudine concentrations 2–4 hours after oral administration was approximately 12%. The true extent of CNS penetration of lamivudine and its relationship with any clinical efficacy is unknown.

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 via UGT1A1 with a minor CYP3A component (9.7% of total dose administered in a human mass balance study). 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).

Metabolism of lamivudine is a minor route of elimination. Lamivudine is predominately cleared by renal excretion of unchanged lamivudine. The likelihood of metabolic drug interactions with lamivudine is low due to the small extent of hepatic metabolism (5–10%).

Drug interactions

In vitro, dolutegravir demonstrated no direct, or weak inhibition (IC50>50 uM) of the enzymes cytochrome P450 (CYP)1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 CYP3A, UGT1A1 or UGT2B7, or the transporters Pgp, BCRP, BSEP, organic anion transporting polypeptide (OATP) 1B1, OATP1B3, OCT1, MATE2-K, multidrug resistance-associated protein (MRP) 2 or MRP4. In vitro, 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 section 4.5).

In vitro, dolutegravir was not a substrate of human OATP 1B1, OATP 1B3 or OCT 1.

In vitro, lamivudine did not inhibit or induce CYP enzymes (such as CYP3A4, CYP2C9 or CYP2D6) and demonstrated no or weak inhibition of OATP1B1, OAT1B3, OCT3, BCRP, P-gp, MATE1 or MATE2-K. Lamivudine is therefore not expected to affect the plasma concentrations of medicinal products that are substrates of these enzymes or transporters.

Lamivudine was not significantly metabolised by CYP enzymes.

Elimination

Dolutegravir has a terminal half-life of ~14 hours. The apparent oral clearance (CL/F) is approximately 1 L/hr in HIV-infected patients based on a population pharmacokinetic analysis.

The observed lamivudine half-life of elimination is 18 to 19 hours. For patients receiving lamivudine 300 mg once daily, the terminal intracellular half-life of lamivudine-TP was 16 to 19 hours. The mean systemic clearance of lamivudine is approximately 0.32 L/h/kg, predominantly by renal clearance (> 70%) via the organic cationic transport system. Studies in patients with renal impairment show lamivudine elimination is affected by renal dysfunction. Dose reduction is required for patients with creatinine clearance < 50 mL/min (see section 4.2).

Pharmacokinetic/phar­macodynamic relationship(s)

In a randomized, dose-ranging trial, HIV-1-infected subjects treated with dolutegravir monotherapy (ING111521) demonstrated rapid and dosedependent 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 group.

Special patient populations

Children

The pharmacokinetics of dolutegravir in 10 antiretroviral treatment-experienced HIV-1 infected adolescents (12 to 17 years) showed that dolutegravir 50 mg once daily dosage resulted in dolutegravir exposure comparable to that observed in adults who received dolutegravir 50 mg once daily.

Limited data are available in adolescents receiving a daily dose of 300 mg of lamivudine. Pharmacokinetic parameters are comparable to those reported in adults.

Elderly

Population pharmacokinetic analysis of dolutegravir using data in HIV-1 infected adults showed that there was no clinically relevant effect of age on dolutegravir exposure.

Pharmacokinetic data for dolutegravir and lamivudine in subjects >65 years of age are limited.

Renal impairment

Pharmacokinetic data have been obtained for dolutegravir and lamivudine separately.

Renal clearance of unchanged active substance is a minor pathway of elimination for dolutegravir. A study of the pharmacokinetics of dolutegravir was performed in subjects with severe renal impairment (CLcr <30 mL/min). No clinically important pharmacokinetic differences between subjects with severe renal impairment (CLcr <30 mL/min) and matching healthy subjects were observed. Dolutegravir has not been studied in patients on dialysis, though differences in exposure are not expected.

Studies with lamivudine show that plasma concentrations (AUC) are increased in patients with renal dysfunction due to decreased clearance.

Based on the lamivudine data, Dovato is not recommended for patients with creatinine clearance of < 50 mL/min.

Hepatic impairment

Pharmacokinetic data has been obtained for dolutegravir and lamivudine separately.

Dolutegravir is primarily metabolized and eliminated by the liver. A single dose of 50 mg of dolutegravir was administered to 8 subjects with moderate hepatic impairment (Child-Pugh class B) and to 8 matched healthy adult controls. While the total dolutegravir concentration in plasma was similar, a 1.5 to 2 fold increase in unbound exposure to dolutegravir was observed in subjects with moderate hepatic impairment compared to healthy controls. No dosage adjustment is considered necessary for patients with mild to moderate hepatic impairment. The effect of severe hepatic impairment on the pharmacokinetics of dolutegravir has not been studied.

Data obtained in patients with moderate to severe hepatic impairment show that lamivudine pharmacokinetics are not significantly affected by hepatic dysfunction.

Polymorphisms in drug metabolising enzymes

There is no evidence that common polymorphisms in drug metabolising enzymes alter dolutegravir pharmacokinetics to a clinically meaningful extent. In a meta-analysis using pharmacogenomics samples collected in clinical studies in healthy subjects, subjects with UGT1A1 (n=7) genotypes conferring poor dolutegravir metabolism had a 32% lower clearance of dolutegravir and 46% higher AUC compared with subjects with genotypes associated with normal metabolism via UGT1A1 (n=41).

Gender

Population PK analyses using pooled pharmacokinetic data from clinical studies where dolutegravir or lamivudine was administered to adults in combination with other ARVs revealed no clinically relevant effect of gender on the exposure of dolutegravir or lamivudine. There is no evidence that a dose adjustment of dolutegravir or lamivudine would be required based on the effects of gender on PK parameters.

Race

Population PK analyses using pooled pharmacokinetic data from clinical studies where dolutegravir was administered to adults in combination with other ARVs revealed no clinically relevant effect of race on the exposure of dolutegravir. The pharmacokinetics of dolutegravir following single dose oral administration to Japanese subjects appear similar to observed parameters in Western (US) subjects. There is no evidence that a dose adjustment of dolutegravir or lamivudine would be required based on the effects of race on PK parameters.

Co-infection with Hepatitis B or C

Population pharmacokinetic analysis indicated that hepatitis C virus coinfection had no clinically relevant effect on the exposure to dolutegravir. There are limited pharmacokinetic data on subjects with hepatitis B coinfection (see section 4.4).

5.3 Preclinical safety data

There are no data available on the effects of the combination of dolutegravir and lamivudine in animals.

Carcinogenesis and mutagenesis

Dolutegravir was not mutagenic or clastogenic using in vitro tests in bacteria and cultured mammalian cells, and an in vivo rodent micronucleus assay.

Lamivudine was not mutagenic in bacterial tests, but consistent with other nucleoside analogues, inhibits cellular DNA replication in in vitro mammalian tests such as the mouse lymphoma assay. The results from two in vivo rat micronucleus tests with lamivudine were negative. Lamivudine has not shown any genotoxic activity in the in vivo studies.

The carcinogenic potential of a combination of dolutegravir and lamivudine has not been tested. Dolutegravir was not carcinogenic in long term studies in the mouse and rat. In long-term oral carcinogenicity studies in rats and mice, lamivudine did not show any carcinogenic potential.

Reproductive toxicology studies

In reproductive toxicity studies in animals, dolutegravir and lamivudine were shown to cross the placenta.

Oral administration of dolutegravir to pregnant rats at doses up to 1000 mg/kg daily from days 6 to 17 of gestation did not elicit maternal toxicity, developmental toxicity or teratogenicity (37.2 times the 50 mg human clinical exposure, based on AUC following single dose in the fasted state). Oral administration of dolutegravir to pregnant rabbits at doses up to 1000 mg/kg daily from days 6 to 18 of gestation did not elicit developmental toxicity or teratogenicity (0.55 times the 50 mg human clinical exposure, based on AUC following single dose in the fasted state). In rabbits, maternal toxicity (decreased food consumption, scant/no faeces/urine, suppressed body weight gain) was observed at 1000 mg/kg (0.55 times the 50 mg human clinical exposure, based on AUC following single dose in the fasted state).

Lamivudine was not teratogenic in animal studies but there were indications of an increase in early embryonic deaths in rabbits at relatively low systemic exposures, comparable to those achieved in humans. A similar effect was not seen in rats even at very high systemic exposure.

Fertility studies in rats have shown that dolutegravir or lamivudine have no effect on male or female fertility.

Repeated dose toxicity

The effect of prolonged daily treatment with high doses of dolutegravir has been evaluated in repeat oral dose toxicity studies in rats (up to 26 weeks) and in monkeys (up to 38 weeks). The primary effect of dolutegravir was gastrointestinal intolerance or irritation in rats and monkeys at doses that produce systemic exposures approximately 28.5 and 1.1 times the 50 mg human clinical exposure following single dose in the fasted state based on AUC, respectively. Because gastrointestinal (GI) intolerance is considered to be due to local active substance administration, mg/kg or mg/m2 metrics are appropriate determinates of safety cover for this toxicity. GI intolerance in monkeys occurred at 30 times the human mg/kg equivalent dose (based on 50 kg human), and 11 times the human mg/m2 equivalent dose for a total daily clinical dose of 50 mg.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Microcrystalline cellulose Sodium starch glycolate Magnesium Stearate Mannitol (E421) Povidone (K29/32) Sodium stearyl fumarate

Tablet coating

Hypromellose (E464) Macrogol

Titanium dioxide (E171)

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

3 years.

6.4 Special precautions for storage

This medicinal product does not require any special storage conditions.

6.5 Nature and contents of container

Opaque, white HDPE (high density polyethylene) bottles closed with child resistant polypropylene closures, with a polyethylene faced induction heat seal liner. Each pack consists of one bottle containing 30 film-coated tablets.

Multipacks containing 90 (3 packs of 30) film-coated tablets.

6.6 Special precautions for disposal

No special requirements for disposal.

7 MARKETING AUTHORISATION HOLDER

ViiV Healthcare UK Limited

980 Great West Road

Brentford

Middlesex

TW8 9GS

United Kingdom

8 MARKETING AUTHORISATION NUMBER(S)

PLGB 35728/0052

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

01/01/2021