1. Name of the medicinal product
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.
3. Pharmaceutical form
Film-coated tablet (tablet)
Purple, biconvex, film-coated oval tablets, approximately 22 x 11 mm, debossed with “572 Trı” on one side.
4. Clinical particulars
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.
Triumeq is a fixed-dose tablet and should not be prescribed for patients requiring dose adjustments. 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.
Missed doses
If the patient misses a dose of Triumeq, the patient should take Triumeq 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 < 50 ml/min (see section 5.2).
Hepatic impairment
A dose reduction of abacavir may be required for patients with mild hepatic impairment (Child-Pugh grade A). As dose reduction is not possible with Triumeq, the separate preparations of dolutegravir, abacavir or lamivudine should be used when this is judged necessary. Triumeq is not recommended in patients with moderate and severe hepatic impairment (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 dolutegravir, abacavir or lamivudine or to any of the excipients listed in section 6.1. See sections 4.4 and 4.8.
Co-administration with dofetilide (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 life-threatening, 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.
Lactic acidosis
Lactic acidosis, usually associated with hepatomegaly and hepatic steatosis, has been reported with the use of nucleoside analogues. Early symptoms (symptomatic hyperlactatemia) include benign digestive symptoms (nausea, vomiting and abdominal pain), non-specific malaise, loss of appetite, weight loss, respiratory symptoms (rapid and/or deep breathing) or neurological symptoms (including motor weakness).
Lactic acidosis has a high mortality and may be associated with pancreatitis, liver failure, or renal failure.
Lactic acidosis generally occurred after a few or several months of treatment.
Treatment with nucleoside analogues should be discontinued in the setting of symptomatic hyperlactatemia and metabolic/lactic acidosis, progressive hepatomegaly, or rapidly elevating aminotransferase levels.
Caution should be exercised when administering nucleoside analogues to any patient (particularly obese women) with hepatomegaly, hepatitis or other known risk factors for liver disease and hepatic steatosis (including certain medicinal products and alcohol). Patients co-infected with hepatitis C and treated with alpha interferon and ribavirin may constitute a special risk.
Patients at increased risk should be followed closely.
Lipodystrophy
Combination antiretroviral therapy has been associated with the redistribution of body fat (lipodystrophy) in HIV patients. The long-term consequences of these events are currently unknown. Knowledge about the mechanism is incomplete. A connection between visceral lipomatosis and protease inhibitors (PIs) and lipoatrophy and nucleoside reverse transcriptase inhibitors (NRTIs) has been hypothesised. A higher risk of lipodystrophy has been associated with individual factors such as older age, and with drug related factors such as longer duration of antiretroviral treatment and associated metabolic disturbances. Clinical examination should include eva luation for physical signs of fat redistribution. Consideration should be given to the measurement of fasting serum lipids and blood glucose. Lipid disorders should be managed as clinically appropriate (see section 4.8).
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 section 4.2).
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 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 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.
As abacavir and ribavirin share the same phosphorylation pathways, a possible intracellular interaction between these medicinal products has been postulated, which could lead to a reduction in intracellular phosphorylated metabolites of ribavirin and, as a possible consequence, a reduced chance of sustained virological response (SVR) for hepatitis C (HCV) in HCV co-infected patients treated with pegylated interferon plus ribavirin. Conflicting clinical findings are reported in literature on co-administration between abacavir and ribavirin. Some data suggest that HIV/HCV co-infected patients receiving abacavir-containing ART may be at risk of a lower response rate to pegylated interferon/ribavirin therapy. Caution should be exercised when medicinal products containing abacavir and ribavirin are co-administered (see section 4.5).
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 carinii pneumonia. Any inflammatory symptoms should be eva luated and treatment instituted when necessary. Autoimmune disorders (such as Graves' disease) 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
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. The main adverse reactions reported are haematological disorders (anaemia, neutropenia), metabolic disorders (hyperlactatemia, hyperlipasemia). These reactions are often transitory. Some late-onset neurological disorders have been reported (hypertonia, convulsion, abnormal behaviour). Whether the neurological disorders are transient or permanent is currently unknown. Any child exposed in utero to nucleoside and nucleotide analogues, even HIV-negative children, should have clinical and laboratory follow-up and should be fully investigated for possible mitochondrial dysfunction in case of relevant signs or symptoms. 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 try to minimize all modifiable risk factors (e.g. smoking, hypertension, and hyperlipidaemia).
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 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.
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
Since the recommended dose of dolutegravir is 50 mg twice daily when co-administered with efavirenz, nevirapine, rifampicin and tipranavir/ritonavir, the use of Triumeq is not recommended for patients taking these medicines (see section 4.5).
The co-administration of Triumeq with etravirine (ETR) is not recommended unless the patient is also receiving concomitant atazanavir+ritonavir (ATV+RTV), lopinavir+ritonavir (LPV+RTV) or darunavir+ritonavir (DRV+RTV) (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 agents (see section 4.5).
Triumeq is recommended to be administered 2 hours before or 6 hours after taking calcium or iron supplements, or alternatively, administered with food (see section 4.5).
Metformin concentrations may be increased by dolutegravir. Patients should be monitored during therapy and a dose adjustment of metformin may be required (see section 4.5).
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.
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 agents on the pharmacokinetics of dolutegravir, abacavir and lamivudine
Dolutegravir is eliminated mainly through metabolism by UGT1A1. Dolutegravir is also a substrate of UGT1A3, UGT1A9, CYP3A4, P-gp, and BCRP. Co-administration of Triumeq and other drugs that inhibit UGT1A1, UGT1A3, UGT1A9, CYP3A4, and/or P-gp may therefore increase dolutegravir plasma concentration. Drugs 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 agents (see Table 1).
Abacavir is metabolised by UDP-glucuronyltransferase (UGT) enzymes and alcohol dehydrogenase; co-administration of inducers or inhibitors 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 organic cation transporter (OCT2) and multidrug and toxin extrusion transporters (MATE1 and MATE-2K). Co-administration of lamivudine with OCT and MATE inhibitors could increase lamivudine exposure. 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 effect on lamivudine exposure in vivo.
Abacavir and lamivudine are not significantly metabolised by CYP enzymes.
Effect of dolutegravir, abacavir and lamivudine on the pharmacokinetics of other agents
In vitro, dolutegravir demonstrated no direct, or weak inhibition (IC50>50 μM) of the enzymes cytochrome P450 (CYP)1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP3A, uridine diphosphate glucuronosyl transferase (UGT)1A1 or UGT2B7, or the transporters Pgp, BCRP, BSEP, OATP1B1, OATP1B3, OCT1, MATE2-K, MRP2 and MRP4. In vitro, dolutegravir did not induce CYP1A2, CYP2B6 or CYP3A4. In vivo, dolutegravir does not seem to have an effect on midazolam, a CYP3A4 probe, however, a weak inhibition cannot be excluded. Based on these data, dolutegravir is not expected to affect the pharmacokinetics of medicinal products that are substrates of these enzymes or transporters.
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 MATE-1 transport) was observed in patients. In vivo, dolutegravir may increase plasma concentrations of medicinal products in which excretion is dependent upon OCT2 or MATE-1 (e.g. dofetilide, 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 medical products in which excretion is dependent upon OAT3.
Abacavir and lamivudine do not inhibit or induce CYP enzymes (such as CYP 3A4, CYP 2C9 or CYP 2D6). In vitro data indicate that inhibition of P-pg and BCRP by abacavir cannot be excluded at intestinal level. In vitro, lamivudine inhibited OCT1 and OCT2.
Established and theoretical interactions with selected antiretrovirals and non-antiretroviral 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 “↑”, decrease as “↓”, no change as “↔”, area under the concentration versus time curve as “AUC”, maximum observed concentration as “Cmax”). The table should not be considered exhaustive but is representative of the classes studied.
Table 1: Drug Interactions

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