TRIUMEQ 50 MG / 600 MG / 300 MG FILM-COATED TABLETS - summary of medicine characteristics

Triumeq 50 mg/600 mg/300 mg film-coated tablets

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each film-coated tablet contains 50 mg dolutegravir (as sodium), 600 mg of abacavir (as sulfate) and 300 mg of lamivudine.

For the full list of excipients see section 6.1.

Film-coated tablet (tablet)

Purple, biconvex, film-coated oval tablets, approximately 22 × 11 mm, debossed with “572 Tri” on one side.

4.1 Therapeutic indications

Triumeq is indicated for the treatment of Human Immunodeficiency Virus (HIV) infected adults and adolescents above 12 years of age weighing at least 40 kg (see sections 4.4 and 5.1).

Before initiating treatment with abacavir-containing products, screening for carriage of the HLA-B*5701 allele should be performed in any HIV-infected patient, irrespective of racial origin (see section 4.4). Abacavir should not be used in patients known to carry the HLA-B*5701 allele.

4.2 Posology and method of administration

Therapy should be prescribed by a physician experienced in the management of HIV infection.

Posology

Adults and adolescents (weighing at least 40kg)

The recommended dose of Triumeq in adults and adolescents is one tablet once daily.

Triumeq should not be administered to adults or adolescents who weigh less than 40 kg because it is a fixed-dose tablet that cannot be dose reduced.

Separate preparations of dolutegravir, abacavir or lamivudine are available in cases where discontinuation or dose adjustment of one of the active substances is indicated. In these cases the physician should refer to the individual product information for these medicinal products. 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).

Missed doses

If the patient misses a dose of Triumeq, the patient should take it 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, abacavir and lamivudine in patients aged 65 years and over. There is no evidence that elderly patients require a different dose than younger adult patients (see section 5.2). Special care is advised in this age group due to age associated changes such as the decrease in renal function and alteration of haematological parameters.

Renal impairment

Triumeq is not recommended for use in patients with a creatinine clearance < 30 mL/min (see section 5.2). No dose adjustment is required in patients with mild or moderate renal impairment. However, the lamivudine exposure is significantly increased in patients with a creatinine clearance < 50 mL/min (see section 4.4).

Hepatic impairment

Abacavir is primarily metabolised by the liver. No clinical data are available in patients with moderate or severe hepatic impairment, therefore the use of Triumeq is not recommended unless judged necessary. In patients with mild hepatic impairment (Child-Pugh score 5–6) close monitoring is required, including monitoring of abacavir plasma levels if feasible (see sections 4.4 and 5.2).

Paediatric population

The safety and efficacy of Triumeq in children less than 12 years of age has not yet been established. No data are available.

Method of administration

Oral use

Triumeq 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. See sections 4.4 and 4.8.

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 (see section 4.8)

Both abacavir and dolutegravir are associated with a risk for hypersensitivity reactions (HSR) (see section 4.8), and share some common features such as fever and/or rash with other symptoms indicating multi-organ involvement. Clinically it is not possible to determine whether a HSR with Triumeq would be caused by abacavir or dolutegravir. Hypersensitivity reactions have been observed more commonly with abacavir, some of which have been lifethreatening, and in rare cases fatal, when not managed appropriately. The risk for abacavir HSR to occur is high for patients who test positive for the HLA-B*5701 allele. However, abacavir HSRs have been reported at a low frequency in patients who do not carry this allele.

Therefore, the following should always be adhered to:

– HLA-B*5701 status must always be documented prior to initiating therapy.

– Triumeq should never be initiated in patients with a positive HLA-B*5701 status, nor in patients with a negative HLA-B*5701 status who had a suspected abacavir HSR on a previous abacavir-containing regimen.

– Triumeq must be stopped without delay, even in the absence of the HLA-B*5701 allele, if an HSR is suspected. Delay in stopping treatment with Triumeq after the onset of hypersensitivity may result in an immediate and life-threatening reaction. Clinical status including liver aminotransferases and bilirubin should be monitored.

– After stopping treatment with Triumeq for reasons of a suspected HSR, Triumeq or any other medicinal product containing abacavir or dolutegravir must never be re-initiated.

– Restarting abacavir containing products following a suspected abacavir HSR can result in a prompt return of symptoms within hours. This recurrence is usually more severe than on initial presentation, and may include life-threatening hypotension and death.

– In order to avoid restarting abacavir and dolutegravir, patients who have experienced a suspected HSR should be instructed to dispose of their remaining Triumeq tablets.

Clinical description of HSRs

Hypersensitivity reactions have been reported in <1% of patients treated with dolutegravir in clinical studies, and were characterized by rash, constitutional findings, and sometimes, organ dysfunction, including severe liver reactions.

Abacavir HSR has been well characterised through clinical studies and during post marketing follow-up. Symptoms usually appeared within the first six weeks (median time to onset 11 days) of initiation of treatment with abacavir, although these reactions may occur at any time during therapy.

Almost all HSR to abacavir will include fever and/or rash. Other signs and symptoms that have been observed as part of abacavir HSR are described in detail in section 4.8 (Description of selected adverse reactions), including respiratory and gastrointestinal symptoms.

Importantly, such symptoms may lead to misdiagnosis of HSR as respiratory disease (pneumonia, bronchitis, pharyngitis), or gastroenteritis. The symptoms related to this HSR worsen with continued therapy and can be life- threatening. These symptoms usually resolve upon discontinuation of abacavir.

Rarely, patients who have stopped abacavir for reasons other than symptoms of HSR have also experienced life-threatening reactions within hours of re- initiating abacavir therapy (see Section 4.8 Description of selected adverse reactions). Restarting abacavir in such patients must be done in a setting where medical assistance is readily available.

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

The safety and efficacy of Triumeq has not been established in patients with significant underlying liver disorders. Triumeq is not recommended in patients with moderate to severe hepatic impairment (see sections 4.2 and 5.2).

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.

Patients with chronic hepatitis B or C

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.

Triumeq includes lamivudine, which is active against hepatitis B. Abacavir and dolutegravir lack 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 Triumeq is used in patients co-infected with hepatitis B an additional antiviral is, therefore, generally needed. Reference should be made to treatment guidelines.

If Triumeq 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.

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 ‘Patients with chronic hepatitis B or C’ 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 HIV-negative 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.

Myocardial infarction

Observational studies have shown an association between myocardial infarction and the use of abacavir. Those studied were mainly antiretroviral experienced patients. Data from clinical trials showed limited numbers of myocardial infarction and could not exclude a small increase in risk. Overall the available data from observational cohorts and from randomised trials show some inconsistency so can neither confirm nor refute a causal relationship between abacavir treatment and the risk of myocardial infarction. To date, there is no established biological mechanism to explain a potential increase in risk. When prescribing Triumeq, action should be taken to minimize all modifiable risk factors (e.g. smoking, hypertension, and hyperlipidaemia).

Osteonecrosis

Although the aetiology is considered to be multifactorial (including corticosteroid use, bisphosphonates, alcohol consumption, severe immunosuppression, higher body mass index), cases of osteonecrosis have been reported particularly 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 Triumeq 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.

Administration in subjects with moderate renal impairment

Patients with a creatinine clearance between 30 and 49 mL/min receiving Triumeq may experience a 1.6-to 3.3-fold higher lamivudine exposure (AUC) than patients with a creatinine clearance >50 mL/min. There are no safety data from randomized, controlled trials comparing Triumeq to the individual components in patients with a creatinine clearance between 30 and 49 mL/min who received dose-adjusted lamivudine. In the original lamivudine registrational trials in combination with zidovudine, higher lamivudine exposures were associated with higher rates of haematologic toxicities (neutropenia and anaemia), although discontinuations due to neutropenia or anaemia each occurred in <1% of subjects. Other lamivudine-related adverse events (such as gastro-intestinal and hepatic disorders) may occur.

Patients with a sustained creatinine clearance between 30 and 49 mL/min who receive Triumeq should be monitored for lamivudine-related adverse events, notably hematologic toxicities. If new or worsening neutropenia or anaemia develop, a dose adjustment of lamivudine, per lamivudine prescribing information, is indicated, which cannot be achieved with T riumeq. Triumeq should be discontinued and the individual components should be used to construct the treatment regimen.

Drug resistance

Since the recommended dose of dolutegravir is 50 mg twice daily for patients with resistance to integrase inhibitors, the use of Triumeq is not recommended for patients with integrase inhibitor resistance.

Drug interactions

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

Triumeq should not be co-administered with polyvalent cation-containing antacids. Triumeq is recommended to be administered 2 hours before or 6 hours after these medicinal products (see section 4.5).

When taken with food, Triumeq and supplements or multivitamins containing calcium, iron or magnesium can be taken at the same time. If Triumeq 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 Triumeq (see section 4.5).

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 section 4.5). 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.

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

Triumeq should not be taken with any other medicinal products containing dolutegravir, abacavir, 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

Triumeq contains dolutegravir, abacavir and lamivudine, therefore any interactions identified for these individually are relevant to Triumeq. No clinically significant drug interactions are expected between dolutegravir, abacavir and lamivudine.

Effect of other medicinal products on the pharmacokinetics of dolutegravir, abacavir 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 Triumeq 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 (see Table 1).

The absorption of dolutegravir is reduced by certain anti-acid medicinal products (see Table 1).

Abacavir is metabolised by UGT (UGT2B7) and alcohol dehydrogenase; coadministration of inducers (e.g. rifampicin, carbamazepine and phenytoin) or inhibitors (e.g. valproic acid) of UGT enzymes or with compounds eliminated through alcohol dehydrogenase could alter abacavir exposure.

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 drug 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 coadministration of dolutegravir based on a cross study analysis, indicating that dolutegravir has no 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 abacavir and lamivudine are substrates of BCRP and P-gp in vitro, given the high absolute bioavailability of abacavir and lamivudine, (see section 5.2), inhibitors of these efflux transporters are unlikely to result in a clinically relevant impact on abacavir or lamivudine concentrations.

Effect of dolutegravir, abacavir 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).

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, abacavir demonstrated the potential to inhibit CYP1A1 and limited potential to inhibit metabolism mediated by CYP3A4. Abacavir was an inhibitor of MATE1; the clinical consequences are not known.

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, abacavir, 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

Potassium channel blockers

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 Triumeq, see below), including consideration of effective contraceptive measures.

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

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 Triumeq, the benefits and risks of continuing Triumeq 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. Triumeq may be used during the second and third trimester of pregnancy when the expected benefit justifies the potential risk to the foetus.

Concerning lamivudine, a large amount of data (more than 5200 outcomes from first trimester) indicates no malformative toxicity. A moderate amount of data (more than 1200 outcomes from first trimester) indicates no malformative toxicity for abacavir.

Abacavir and lamivudine may inhibit cellular DNA replication and abacavir has been shown to be carcinogenic in animal models (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.

Abacavir and its metabolites are excreted into the milk of lactating rats. Abacavir is also excreted into human milk.

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

4.7 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 Triumeq 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 considered possibly or probably related to dolutegravir and abacavir/lamivudine were nausea (12%), insomnia (7%), dizziness (6%) and headache (6%).

Many of the adverse reactions listed in the table below occur commonly (nausea, vomiting, diarrhoea, fever, lethargy, rash) in patients with abacavir hypersensitivity. Therefore, patients with any of these symptoms should be carefully evaluated for the presence of this hypersensitivity (see section 4.4). Very rarely cases of erythema multiforme, Stevens-Johnson syndrome or toxic epidermal necrolysis have been reported where abacavir hypersensitivity could not be ruled out. In such cases medicinal products containing abacavir should be permanently discontinued.

The most severe adverse event possibly related to the treatment with dolutegravir and abacavir/lami­vudine, seen in individual patients, was a hypersensitivity reaction that included rash and severe liver effects (see section 4.4 and Description of selected adverse reactions in this section).

Tabulated list of adverse reactions

The adverse reactions considered at least possibly related to treatment with the components of Triumeq 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 (> 1/1000 to < 1/100), rare (> 1/10,000 to < 1/1000), very rare (< 1/10,000).

Table 2:      Tabulated summary of adverse reactions associated with the

combination of dolutegravir + abacavir/lamivudine in an analysis of pooled data from: Phase IIb to Phase IIIb clinical trials or post-marketing experience; and adverse reactions to treatment with dolutegravir, abacavir and lamivudine from clinical studies and post-marketing experience when used with other antiretrovirals

Description of selected adverse reactions

Hypersensitivity reactions

Both abacavir and dolutegravir are associated with a risk for hypersensitivity reactions (HSR), which were observed more commonly with abacavir.

Hypersensitivity reaction observed for each of these medicinal products (described below) share some common features such as fever and/or rash with other symptoms indicating multi-organ involvement. Time to onset was typically 10–14 days for both abacavir and dolutegravir-associated reactions, although reactions to abacavir may occur at any time during therapy.

Treatment with Triumeq must be stopped without delay if HSR cannot be ruled out on clinical grounds, and therapy with Triumeq or other abacavir or dolutegravir containing products must never be re-initiated. Please refer to section 4.4 for further details on patient management in the event of a suspected HSR to Triumeq.

Dolutegravir hypersensitivity

Symptoms have included rash, constitutional findings, and sometimes, organ dysfunction, including severe liver reactions.

Abacavir hypersensitivity

The signs and symptoms of this HSR are listed below. These have been identified either from clinical studies or post marketing surveillance. Those reported in at least 10% of patients with a hypersensitivity reaction are in bold text.

Almost all patients developing hypersensitivity reactions will have fever and/or rash (usually maculopapular or urticarial) as part of the syndrome, however reactions have occurred without rash or fever. Other key symptoms include gastrointestinal, respiratory or constitutional symptoms such as lethargy and malaise.

Skin

Rash (usually maculopapular or urticarial)

Symptoms related to this HSR worsen with continued therapy and can be lifethreatening and in rare instance, have been fatal.

Restarting abacavir following an abacavir HSR results in a prompt return of symptoms within hours. This recurrence of the HSR is usually more severe than on initial presentation, and may include life-threatening hypotension and death. Similar reactions have also occurred infrequently after restarting abacavir in patients who had only one of the key symptoms of hypersensitivity (see above) prior to stopping abacavir; and on very rare occasions have also been seen in patients who have restarted therapy with no preceding symptoms of a HSR (i.e., patients previously considered to be abacavir tolerant).

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 reactivation syndrome

In HIV-infected patients with severe immune deficiency at the time of initiation of 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).

Changes in laboratory chemistries

Increases in serum creatinine occurred within the first week of treatment with dolutegravir and remained stable through 96 weeks. In the SINGLE study a mean change from baseline of 12.6 Limol/I. was observed after 96 weeks of treatment. These changes are not considered to be clinically relevant since they do not reflect a change in glomerular filtration rate.

Asymptomatic creatine phosphokinase (CPK) elevations mainly in association with exercise have also been reported with dolutegravir therapy.

Co-infection with Hepatitis B or C

In dolutegravir Phase III studies 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 coinfection for all treatment groups.

Paediatric population

There are no clinical study data on the effects of Triumeq 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 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.

The individual preparations of abacavir and lamivudine have been investigated separately, and as a dual nucleoside backbone, in combination antiretroviral therapy to treat ART- naive and ART- experienced HIV- infected paediatric patients (data available on the use of abacavir and lamivudine in infants less than three months are limited). No additional types of adverse reactions have been observed beyond those characterised for 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: 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, abacavir or lamivudine, 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 Triumeq. 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. It is not known whether abacavir can be removed by peritoneal dialysis or haemodialysis. 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: J05AR13

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.

Abacavir and lamivudine are potent selective inhibitors of HIV-1 and HIV-2. Both abacavir and lamivudine are metabolised sequentially by intracellular kinases to the respective 5'-triphosphates (TP) which are the active moieties with extended intracellular half-lives supporting once daily dosing (see section 5.2). Lamivudine-TP (an analogue for cytidine) and carbovir-TP (the active triphosphate form of abacavir, an analogue for guanosine) are substrates for and competitive inhibitors of HIV reverse transcriptase (RT). However, their main antiviral activity is through incorporation of the monophosphate form into the viral DNA chain, resulting in chain termination. Abacavir and lamivudine triphosphates show significantly less affinity for host cell DNA polymerases.

Pharmacodynamic effects

Antiviral activity in vitro

Dolutegravir, abacavir 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 mean IC50 for abacavir against lab-strains of HIV-1IIIB and HIV-1HXB2 ranged from 1.4 to 5.8 UM. The median or mean IC50 values for lamivudine against lab-strains of HIV-1 ranged from 0.007 to 2.3 UM. The mean IC50 against lab-strains of HIV-2 (LAV2 and EHO) ranged from 1.57 to 7.5 UM for abacavir and from 0.16 to 0.51 UM for lamivudine.

The IC50 values of abacavir against HIV-1 Group M subtypes (A-G) ranged from 0.002 to 1.179 UM, against Group O from 0.022 to 1.21 UM, and against HIV-2 isolates, from 0.024 to 0.49 UM. For lamivudine, the IC50 values against HIV-1 subtypes (A-G) ranged from 0.001 to 0.170 UM, against Group O from 0.030 to 0.160 UM and against HIV-2 isolates from 0.002 to 0.120 UM 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 abacavir (IC50 fold changes < 2.5), and lamivudine (IC50 fold changes < 3.0), except for two CRF02_AG isolates with fold changes of 2.9 and 3.4 for abacavir. Group O isolates from antiviral naïve patients tested for lamivudine activity were highly sensitive.

The combination of abacavir and lamivudine has demonstrated antiviral activity in cell culture against non-subtype B isolates and HIV-2 isolates with equivalent antiviral activity as for subtype B isolates.

Antiviral activity in combination with other antiviral agents

No antagonistic effects in vitro were seen with dolutegravir and other antiretrovirals (tested agents: stavudine, abacavir, efavirenz, nevirapine, lopinavir, amprenavir, enfuvirtide, maraviroc, adefovir and raltegravir). In addition, ribavirin had no apparent effect on dolutegravir activity.

The antiviral activity of abacavir in cell culture was not antagonized when combined with the nucleoside reverse transcriptase inhibitors (NRTIs) didanosine, emtricitabine, lamivudine, stavudine, tenofovir, zalcitabine or zidovudine, the non-nucleoside reverse transcriptase inhibitor (NNRTI) nevirapine, or the protease inhibitor (PI) amprenavir.

No antagonistic effects in vitro were seen with lamivudine and other antiretrovirals (tested agents: abacavir, didanosine, nevirapine, zalcitabine, and zidovudine).

Effect of human serum

In 100% human serum, the mean fold shift for dolutegravir activity was 75fold, resulting in protein adjusted IC90 of 0.064 ug/mL. Plasma protein binding studies in vitro indicate that abacavir binds only low to moderately (~49%) to human plasma proteins at therapeutic concentrations. Lamivudine exhibits linear pharmacokinetics over the therapeutic dose range and displays low plasma protein binding (less than 36%).

Resistance

Resistance in vitro: (dolutegravir)

Serial passage is used to study resistance evolution in vitro. When using the lab-strain HIVIII during passage over 112 days, mutations selected appeared slowly, with substitutions at positions S153Y and F. These mutations were not selected in patients treated with dolutegravir in the clinical studies. Using strain NL432 mutations E92Q (fold change 3) and G193E (fold change 3) were selected. These mutations have been selected in patients with preexisting raltegravir resistance and who were then treated with dolutegravir (listed as secondary mutations for dolutegravir).

In further selection experiments using clinical isolates of subtype B, mutation R263K was seen in all five isolates (after 20 weeks and onwards). In subtype C (n=2) and A/G (n=2) isolates the integrase substitution R263K was selected in one isolate, and G118R in two isolates. R263K was reported from two individual patients with subtype B and subtype C in the clinical program for ART experienced, INI naive subjects, but without effects on dolutegravir susceptibility in vitro. G118R lowers the susceptibility to dolutegravir in site directed mutants (fold change 10), but was not detected in patients receiving dolutegravir in the Phase III program.

Primary mutations for raltegravir/el­vitegravir (Q148H/R/K, N155H, Y143R/H/C, E92Q, T66I) do not affect the in vitro susceptibility of dolutegravir as single mutations. When mutations listed as secondary integrase inhibitor associated mutations (for raltegravir/el­vitegravir) are added to primary mutations (excluding at Q148) in experiments with site directed mutants, dolutegravir susceptibility remains at or near wildtype level. In the case of the Q148-mutation viruses, increasing dolutegravir fold change is seen as the number of secondary mutations increase. The effect of the Q148-based mutations (H/R/K) was also consistent with in vitro passage experiments with site directed mutants. In serial passage with strain NL432-based site directed mutants at N155H or E92Q, no further selection of resistance was seen (fold change unchanged around 1). In contrast, starting passage with mutants with mutation Q148H (fold change 1), a variety of raltegravir associated secondary mutations accumulated with a consequent increase of fold change to values >10.

A clinically relevant phenotypic cut-off value (fold change vs wild type virus) has not been determined; genotypic resistance was a better predictor for outcome.

Seven hundred and five raltegravir resistant isolates from raltegravir experienced patients were analyzed for susceptibility to dolutegravir. Dolutegravir has a <10-fold change against 94% of the 705 clinical isolates.

Resistance in vivo: (dolutegravir)

In previously untreated patients receiving dolutegravir + 2 NRTIs in Phase IIb and Phase III, no development of resistance to the integrase class, or to the NRTI class was seen (n=876, follow-up of 48–96 weeks).

In patients with prior failed therapies, but naïve to the integrase class (SAILING study), integrase inhibitor substitutions were observed in 4/354 patients (follow-up 48 weeks) treated with dolutegravir, which was given in combination with an investigator selected background regimen (BR). Of these four, two subjects had a unique R263K integrase substitution, with a maximum fold change of 1.93, one subject had a polymorphic V151V/I integrase substitution, with maximum fold change of 0.92, and one subject had pre-existing integrase mutations and is assumed to have been integrase experienced or infected with integrase resistant virus by transmission. The R263K mutation was also selected in vitro (see above).

Resistance in vitro and in vivo: (abacavir and lamivudine) Abacavir-resistant isolates of HIV-1 have been selected in vitro and in vivo and are associated with specific genotypic changes in the RT codon region (codons M184V, K65R, L74V and Y115F). During in vitro abacavir selection the M184V mutation occurred first and resulted in about a 2-fold increase in IC50, below the abacavir clinical cut-off of 4.5-fold change. Continued passage in increasing concentrations of drug resulted in selection for double RT mutants 65R/184V and 74V/184V or triple RT mutant 74V/115Y/184V. Two mutations conferred a 7 to 8-fold change in abacavir susceptibility and combinations of three mutations were required to confer more than an 8-fold change in susceptibility.

HIV-1 resistance to lamivudine involves the development of a M184I or M184V amino acid change close to the active site of the viral RT. This variant arises both in vitro and in HIV-1 infected patients treated with lamivudine-containing antiretroviral therapy. M184V mutants display greatly reduced susceptibility to lamivudine and show diminished viral replicative capacity in vitro. M184V is associated with about a 2-fold increase in abacavir resistance but does not confer clinical resistance for abacavir.

Isolates resistant to abacavir may also show reduced sensitivity to lamivudine. The combination of abacavir/lamivudine has demonstrated decreased susceptibility to viruses with the substitutions K65R with or without the M184V/I substi­tution, and to viruses with L74V plus the M184V/I

substitution.

Cross-resistance between dolutegravir or abacavir or lamivudine and antiretrovirals from other classes e.g. PIs or NNRTIs is unlikely.

Effects on electrocardiogram

No relevant effects were seen on the QTc interval, with doses of dolutegravir exceeding the clinical dose by approximately 3-fold. Similar studies were not conducted with either abacavir or lamivudine.

Clinical efficacy and safety

The efficacy of Triumeq in HIV-infected, therapy naive subjects is based on the analyses of data from a number of trials. The analyses included two randomized, international, double-blind, active-controlled trials, SINGLE (ING114467) and SPRING-2 (ING113086), the international, open-label, active-controlled trial FLAMINGO (ING114915), and the randomized, openlabel, active-controlled, multicentre, non-inferiority study ARIA (ING117172).

The STRIIVING study (201147), was a randomized, open-label, active-controlled, multicentre, non-inferiority switch study in virologically suppressed subjects with no documented history of resistance to any class.

In SINGLE, 833 patients were treated with dolutegravir 50 mg once daily plus fixed-dose abacavir-lamivudine (DTG + ABC/3TC) or fixed-dose efavirenz-tenofovir-emtricitabine (EFV/TDF/FTC). At baseline, median patient age was 35 years, 16% were female, 32% non-white, 7% had hepatitis C co-infection and 4% were CDC Class C, these characteristics were similar between treatment groups. Week 48 outcomes (including outcomes by key baseline covariates) are shown in Table 3.

Table 3:      Virologic Outcomes of Randomized Treatment of SINGLE at

48 Weeks (Snapshot        algorithm)

In the primary 48 weeks analysis, the proportion of patients with virologic suppression in the dolutegravir + ABC/3TC arm, was superior to the EFV/TDF/FTC arm, p=0.003, the same treatment difference was observed in subjects defined by baseline HIV RNA level (< or > 100,000 copi­es/mL). The median time to viral suppression was shorter with ABC/3TC + DTG (28 vs 84 days, p<0.0001). The adjusted mean change in CD4+ T cell count from baseline were 267 cells versus 208 cells/mm3, respectively (p<0.001). Both the time to viral suppression and change from baseline analyses were prespecified and adjusted for multiplicity. At 96 weeks, the response was 80% vs 72%, respectively. The difference in the endpoint remained statistically significant (p=0.006). The statistically higher responses on DTG+ABC/3TC were driven by a higher rate of withdrawals due to AEs in the EFV/TDF/FTC arm, irrespective of viral load strata. Overall treatment differences at Week 96 are applicable to patients with high and low Baseline viral loads. At 144 weeks in the open-label phase of SINGLE, virologic suppression was maintained, the

DTG +ABC/3TC arm (71%) was superior to the EFV/TDF/FTC arm (63%), treatment difference was 8.3% (2.0, 14.6).

In SPRING-2, 822 patients were treated with either dolutegravir 50 mg once daily or raltegravir 400 mg twice daily (blinded), both with fixed-dose ABC/3TC (around 40%) or TDF/FTC (around 60%), given open label.

Baseline demographics and outcomes are summarised in Table 4.

Dolutegravir was non-inferior to raltegravir, including within the subset of patients with the abacavir/lamivudine background regimen.

Table 4: Demographics and virologic outcomes of randomized treatment of SPRING-2 (snapshot algorithm)

In FLAMINGO, 485 patients were treated with dolutegravir 50 mg once daily or darunavir/ritonavir (DRV/r) 800 mg/100 mg once daily, both with ABC/3TC (around 33%) or TDF/FTC (around 67%). All treatments were given open-label. Main demographics and outcomes are summarised in Table 5.

Table 5: Demographics and Week 48 virologic outcomes of randomized treatment of FLAMINGO (snapshot algorithm)

At 96 weeks, virologic suppression in the dolutegravir group (80%) was superior to the DRV/r group (68%), (adjusted treatment difference [DTG-(DRV+RTV)]: 12.4%; 95% CI: [4.7, 20.2]). Response rates at 96 weeks were 82% for DTG+ABC/3TC and 75% for DRV/r+ABC/3TC.

In ARIA (ING117172), a randomized, open-label, active-controlled, multicenter, parallel group, non-inferiority study; 499 HIV-1 infected ART naïve adult women were randomized 1:1 to receive either; DTG/ABC/3TC FDC 50 mg/600 mg/300 mg; or atazanavir 300 mg plus ritonavir 100 mg plus tenofovir disproxil / emtricitabine 245 mg/200 mg (ATV+RTV+TDF/FTC FDC), all administered once daily.

Table 6: Demographics and Week 48 virologic outcomes of randomized treatment of ARIA

(snapshot algorithm)

STRIIVING (201147) is a 48-week, randomized, open-label, active controlled, multicenter, non-inferiority study in patients without any prior treatment failure, and without any documented resistance to any class. Virologically suppressed (HIV-1 RNA <50 c/mL) subjects were randomly assigned (1:1) to continue their current ART regimen (2 NRTIs plus either a PI, NNRTI, or INI), or switch to ABC/DTG/3TC FDC once daily (Early Switch). Hepatitis B co-infection was one of main exclusion criteria.

Patients were mainly white (66%) or black (28%) of male sex (87%). Main prior transmission routes were homosexual (73%) or heterosexual (29%) contact. The proportion with a positive HCV serology was 7%. The median time from first starting ART was around 4.5 years.

Table 7: Outcomes of randomized treatment of STRIIVING (snapshot algorithm)

Virologic suppression (HIV-1 RNA <50 copies/mL) in the ABC/DTG/3TC FDC group (85%) was statistically non-inferior to the current ART groups (88%) at 24 weeks. The adjusted difference in proportion and 95% CI [ABC/DTG/3TC vs current ART] were 3.4%; 95% CI: [-9.1, 2.4]. After 24 weeks all remaining subjects switched to ABC/DTG/3TC FDC (Late Switch). Similar levels of virologic suppression were maintained in both the Early and Late Switch groups at 48 weeks.

De novo resistance in patients failing therapy in SINGLE, SPRING-2 and FLAMINGO

De novo resistance was not detected to the integrase class or the NRTI class in any patients who were treated with dolutegravir + abacavir/lamivudine in the three studies mentioned.

For the comparators typical resistance was detected with TDF/FTC/EFV (SINGLE; six with NNRTI associated resistance and one with major NRTI resistance) and with 2 NRTIs + raltegravir (SPRING-2; four with major NRTI resistance and one with raltegravir resistance), while no de novo resistance was detected in patients treated with 2 NRTIs + DRV/RTV (FLAMINGO).

Paediatric population

In a Phase I/II 48 week multicentre, open-label study (P1093/ING112578), the pharmacokinetic parameters, safety, tolerability and efficacy of dolutegravir was evaluated in combination regimens in HIV-1 infected infants, children and adolescents.

At 24 weeks, 16 of 23 (69%) adolescents (12 to 17 years of age) treated with dolutegravir once daily (35 mg n=4; 50 mg n=19) plus OBR achieved viral load less than 50 copies/mL.

Twenty out of 23 children and adolescents (87%) had >1 log10 c/mL decrease from Baseline in HIV-1 RNA or HIV-1 RNA <400 c/mL at Week 24. Four subjects had virologic failure none of which had INI resistance at the time of virologic failure.

5.2 Pharmacokinetic properties

The Triumeq tablet has been shown to be bioequivalent to dolutegravir single entity tablet and abacavir/lamivudine fixed-dose combination tablet (ABC/3TC FDC) administered separately. This was demonstrated in a single dose, 2-way crossover bioequivalence study of Triumeq (fasted) versus 1 × 50 mg dolutegravir tablet, plus 1 × 600mg abacavir/300 mg lamivudine tablet (fasted) in healthy subjects (n=66). The effect of a high fat meal on the Triumeq tablet was evaluated in a subgroup of subjects in this study (n=12). Plasma Cmax and AUC of dolutegravir following administration of Triumeq with a high fat meal were 37% and 48% higher, respectively, than those following administration of Triumeq in the fasted state. This is not considered clinically significant (see Absorption). The effect of food on plasma exposures of abacavir and lamivudine following administration of Triumeq with a high fat meal were very similar to prior food effects observed with ABC/3TC FDC. These results indicate that Triumeq can be taken with or without food.

The pharmacokinetic properties of dolutegravir, lamivudine and abacavir are described below.

Absorption

Dolutegravir, abacavir and lamivudine are rapidly absorbed following oral administration. The absolute bioavailability of dolutegravir has not been established. The absolute bioavailability of oral abacavir and lamivudine in adults is about 83% and 80–85% respectively. The mean time to maximal serum concentrations (tmax) is about 2 to 3 hours (post dose for tablet formulation), 1.5 hours and 1.0 hour for dolutegravir, abacavir and lamivudine, respectively.

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) pg.h/mL, Cmax = 3.67 (20) pg/mL, and Cmin = 1.11 (46) pg/mL. Following a single dose of 600 mg of abacavir, the mean (CV) Cmax is 4.26 pg/ml (28%) and the mean (CV) AUC, is 11.95 pg.h/ml (21%). Following multiple-dose oral administration of lamivudine 300 mg once daily for seven days, the mean (CV) steady-state Cmax is 2.04 pg/ml (26%) and the mean (CV) AUC24 is 8.87 pg.h/ml (21%).

Plasma Cmax and AUC of dolutegravir following administration of Triumeq with a high fat meal were 37% and 48% higher, respectively, than those following administration of Triumeq in the fasted state). For abacavir there was a decrease in Cmax with 23% and AUC was unchanged. The exposure of lamivudine was similar with and without food. These results indicate that Triumeq can be taken with or without food.

Distribution

The apparent volume of distribution of dolutegravir (following oral administration of suspension formulation, Vd/F) is estimated at 12.5 L. Intravenous studies with abacavir and lamivudine showed that the mean apparent volume of distribution is 0.8 and 1.3 l/kg respectively.

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. Plasma protein binding studies in vitro indicate that abacavir binds only low to moderately (~49%) to human plasma proteins at therapeutic concentrations. Lamivudine exhibits linear pharmacokinetics over the therapeutic dose range and displays limited plasma protein binding in vitro (< 36%).

Dolutegravir, abacavir 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). Studies with abacavir demonstrate a CSF to plasma AUC ratio of between 30 to 44%. The observed values of the peak concentrations are 9-fold greater than the IC50 of abacavir of 0.08 ng/ml or 0.26 ^M when abacavir is given at 600 mg twice daily. 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).

Abacavir is primarily metabolised by the liver with approximately 2% of the administered dose being renally excreted, as unchanged compound. The primary pathways of metabolism in man are by alcohol dehydrogenase and by glucuronidation to produce the 5’-carboxylic acid and 5’-glucuronide which account for about 66% of the administered dose. These metabolites are excreted in the urine.

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 jiM) 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 1B1 (OATP1B1), OATP1B3, OCT1, MATE2-K, multidrug resistance-associated protein 2 (MRP2) 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, abacavir did not inhibit or induce CYP enzymes (other than CY1A1 and CYP3A4 [limited potential], see section 4.5) and demonstrates no or weak inhibition of OATP1B1, OAT1B3, OCT1, OCT2, BCRP and P-gp or MATE2-K. Abacavir is therefore not expected to affect the plasma concentrations of drugs that are substrates of these enzymes or transporters.

Abacavir was not significantly metabolised by CYP enzymes. In vitro, abacavir was not a substrate of OATP1B1, OATP1B3, OCT1, OCT2, OAT1, MATE1, MATE2-K, MRP2 or MRP4 therefore drugs that modulate these transporters are not expected to affect abacavir plasma concentrations.

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 drugs 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 mean half-life of abacavir is about 1.5 hours. The geometric mean terminal halflife of intracellular active moiety carbovirtriphos­phate (TP) at steady-state is 20.6 hours. Following multiple oral doses of abacavir 300 mg twice a day there is no significant accumulation of abacavir. Elimination of abacavir is via hepatic metabolism with subsequent excretion of metabolites primarily in the urine. The metabolites and unchanged abacavir account for about 83% of the administered abacavir dose in the urine. The remainder is eliminated in the faeces.

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 < 30 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 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 group.

Intracellular pharmacokinetics

The geometric mean terminal carbovir-TP intracellular half-life at steady-state was 20.6 hours, compared to the geometric mean abacavir plasma half-life of 2.6 hours. The terminal intracellular half-life of lamivudine-TP was prolonged to 16–19 hours, compared to the plasma lamivudine half-life of 5–7 hours, supporting once daily dosing of ABC and 3TC.

Special patient populations

Hepatic impairment

Pharmacokinetic data has been obtained for dolutegravir, abacavir 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.

Abacavir is metabolised primarily by the liver. The pharmacokinetics of abacavir have been studied in patients with mild hepatic impairment (Child-Pugh score 5–6) receiving a single 600 mg dose. The results showed that there was a mean increase of 1.89-fold [1.32; 2.70] in the abacavir AUC, and 1.58 [1.22; 2.04] fold in the elimination half-life. No recommendation on dose reduction is possible in patients with mild hepatic impairment due to substantial variability of abacavir exposure.

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

Based on data obtained for abacavir, Triumeq is not recommended in patients with moderate and severe hepatic impairment.

Renal impairment

Pharmacokinetic data have been obtained for dolutegravir, lamivudine and abacavir 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.

Abacavir is primarily metabolised by the liver with approximately 2% of abacavir excreted unchanged in the urine. The pharmacokinetics of abacavir in patients with end-stage renal disease is similar to patients with normal renal function.

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

Based on the lamivudine data, Triumeq is not recommended for patients with creatinine clearance of < 30 mL/min.

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, abacavir and lamivudine in subjects >65 years of age are limited.

Paediatric population

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 600 mg of abacavir and 300 mg of lamivudine. Pharmacokinetic parameters are comparable to those reported in adults.

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 metaanalysis 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 Phase IIb and Phase III adult trials revealed no clinically relevant effect of gender on the exposure of dolutegravir. There is no evidence that a dose adjustment of dolutegravir, abacavir or lamivudine would be required based on the effects of gender on PK parameters.

Race

Population PK analyses using pooled pharmacokinetic data from Phase IIb and Phase III adult trials 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, abacavir 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 co-infection had no clinically relevant effect on the exposure to dolutegravir. There are limited pharmacokinetic data on subjects with hepatitis B co-infection (see section 4.4).

5.3 Preclinical safety data

There are no data available on the effects of the combination of dolutegravir, abacavir and lamivudine in animals, except a negative in vivo rat micronucleus test which tested the effects of the combination of abacavir and lamivudine.

Mutagenicity and carcinogenicity

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

Neither abacavir nor lamivudine were mutagenic in bacterial tests, but consistent with other nucleoside analogues, inhibit cellular DNA replication in in vitro mammalian tests such as the mouse lymphoma assay. The results of an in vivo rat micronucleus test with abacavir and lamivudine in combination were negative.

Lamivudine has not shown any genotoxic activity in the in vivo studies. Abacavir has a weak potential to cause chromosomal damage both in vitro and in vivo at high tested concentrations.

The carcinogenic potential of a combination of dolutegravir, abacavir 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. Carcinogenicity studies with orally administered abacavir in mice and rats showed an increase in the incidence of malignant and non-malignant tumours. Malignant tumours occurred in the preputial gland of males and the clitoral gland of females of both species, and in rats in the thyroid gland of males and in the liver, urinary bladder, lymph nodes and the subcutis of females.

The majority of these tumours occurred at the highest abacavir dose of 330 mg/kg/day in mice and 600 mg/kg/day in rats. The exception was the preputial gland tumour which occurred at a dose of 110 mg/kg in mice. The systemic exposure at the no effect level in mice and rats was equivalent to 3 and 7 times the human systemic exposure during therapy. While the clinical relevance of these findings is unknown, these data suggest that a potential carcinogenic risk to humans is outweighed by the clinical benefit.

Repeat-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 38 and 1.5 times the 50 mg human clinical exposure 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 2 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.

In toxicology studies abacavir was shown to increase liver weights in rats and monkeys. The clinical relevance of this is unknown. There is no evidence from clinical studies that abacavir is hepatotoxic. Additionally, autoinduction of abacavir metabolism or induction of the metabolism of other medicinal products hepatically metabolised has not been observed in humans.

Mild myocardial degeneration in the heart of mice and rats was observed following administration of abacavir for two years. The systemic exposures were equivalent to 7 to 21 times the expected systemic exposure in humans. The clinical relevance of this finding has not been determined.

Reproductive toxicology

In reproductive toxicity studies in animals, dolutegravir, lamivudine and abacavir 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 (50 times the 50 mg human clinical exposure when administered in combination with abacavir and lamivudine based on AUC).

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 (0.74 times the 50mg human clinical exposure when administered in combination with abacavir and lamivudine based on AUC). In rabbits, maternal toxicity (decreased food consumption, scant/no faeces/urine, suppressed body weight gain) was observed at 1000 mg/kg (0.74 times the

50 mg human clinical exposure when administered in combination with abacavir and lamivudine based on AUC).

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.

Abacavir demonstrated toxicity to the developing embryo and foetus in rats, but not in rabbits. These findings included decreased foetal body weight, foetal oedema, and an increase in skeletal variations/mal­formations, early intrauterine deaths and still births. No conclusion can be drawn with regard to the teratogenic potential of abacavir because of this embryo-foetal toxicity.

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

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Tablet core

Mannitol (E421)

Microcrystalline cellulose

Povidone (K29/32)

Sodium starch glycollate

Magnesium stearate

Tablet coating

Poly(vinyl) alcohol – partially hydrolysed titanium dioxide

macrogol

talc

iron oxide black

iron oxide red

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

3 years

6.4 Special precautions for storage

Store in the original package in order to protect from moisture. Keep the bottle tightly closed. Do not remove the desiccant.

This medicinal product does not require any special temperature storage conditions.

6.5 Nature and contents of container

White HDPE (high density polyethylene) bottles closed with polypropylene child-resistant closures, with a polyethylene faced induction heat seal liner. Each bottle contains 30 film-coated tablets and a desiccant.

Multipacks containing 90 (3 packs of 30) film-coated tablets. Each pack of 30 film-coated tablets contains a desiccant.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.