4.1. Therapeutic indications

Triumeq is indicated for the treatment of Human Immunodeficiency Virus type 1 (HIV-1) infected adults, adolescents and children weighing at least 25 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, adolescents and children (weighing at least 25kg)

The recommended dose is one tablet once daily.

Triumeq film-coated tablets should not be administered to adults, adolescents or children who weigh less than 25 kg because it is a fixed‑dose tablet that cannot be dose reduced. Triumeq dispersible tablets should be administered to children of at least 3 months of age and weighing at least 6 kg to less than 25 kg.

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 dose of dolutegravir (film-coated tablets or dispersible tablets) is applicable 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).

Dispersible tablets

Triumeq is available as dispersible tablets for patients of at least 3 months of age and weighing at least 6 kg to less than 25 kg. The bioavailability of dolutegravir from film-coated tablets and dispersible tablets is not comparable; therefore, they must not be used as direct replacements (see section 5.2).

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.

Special populations

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 3 months of age or weighting less than 6 kg have not yet been established.

Currently available data are described in section 4.8, 5.1 and 5.2, but no recommendation on a posology can be made.

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.

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

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.

Weight and metabolic parameters

An increase in weight and in levels of blood lipids and glucose may occur during antiretroviral therapy. Such changes may in part be linked to disease control and lifestyle. For lipids and weight, there is in some cases evidence for a treatment effect. 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.

Cardiovascular events

Although the available data from clinical and observational studies with abacavir show inconsistent results, several studies suggest an increased risk of cardiovascular events (notably myocardial infarction) in patients treated with abacavir. Therefore, when prescribing Triumeq, action should be taken to minimize all modifiable risk factors (e.g. smoking, hypertension, and hyperlipidaemia). In addition, alternative treatment options to the abacavir containing regimen should be considered when treating patients with a high cardiovascular risk.

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 randomised, 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

The use of Triumeq is not recommended for patients with integrase inhibitor resistance. This is because the recommended dose of dolutegravir is 50 mg twice daily for adult patients with resistance to integrase inhibitors and there are insufficient data to recommend a dose of dolutegravir in integrase inhibitor resistant adolescents, children and infants.

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).

Excipients

Triumeq contains less than 1 mmol sodium (23 mg) per tablet, that is to say is essentially 'sodium free'.

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; co-administration 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 co-administration 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 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“, concentration at end of dosing interval as “C“). The table should not be considered exhaustive but is representative of the classes studied.

Table 1: Drug interactions

Medicinal products by therapeutic areas

Interaction geometric mean change (%)

Recommendations concerning co-administration

Antiretroviral medicinal products

Non-nucleoside reverse transcriptase inhibitors (Non-NRTIs)

Etravirine without boosted protease inhibitors / Dolutegravir

Dolutegravir ↓   AUC ↓ 71%   Cmax ↓ 52%  C ↓ 88%

Etravirine ↔

(induction of UGT1A1 and CYP3A enzymes)

Etravirine without boosted protease inhibitors decreased plasma dolutegravir concentration. The recommended dose of dolutegravir is 50 mg twice daily for patients taking etravirine without boosted protease inhibitors. As Triumeq is a fixed dose tablet, an additional 50 mg tablet of dolutegravir should be administered, approximately 12 hours after Triumeq for the duration of the etravirine without boosted protease inhibitor co-administration (a separate preparation of dolutegravir is available for this dose adjustment, see section 4.2).

Lopinavir+ritonavir+etravirine/ Dolutegravir

Dolutegravir ↔  AUC ↑ 11%  Cmax ↑ 7%  C ↑ 28%

Lopinavir ↔Ritonavir ↔Etravirine ↔

No dose adjustment is necessary.

Darunavir+ritonavir+etravirine/ Dolutegravir

Dolutegravir ↓  AUC ↓ 25%  Cmax ↓ 12%  C ↓ 36%

Darunavir ↔Ritonavir ↔Etravirine ↔

No dose adjustment is necessary.

Efavirenz/Dolutegravir

Dolutegravir ↓   AUC ↓ 57%   Cmax ↓ 39%  C ↓ 75%

Efavirenz ↔ (historical controls)

(induction of UGT1A1 and CYP3A enzymes)

The recommended dose of dolutegravir is 50 mg twice daily when co-administered with efavirenz. As Triumeq is a fixed dose tablet, an additional 50 mg tablet of dolutegravir should be administered, approximately 12 hours after Triumeq for the duration of the efavirenz co-administration (a separate preparation of dolutegravir is available for this dose adjustment, see section 4.2).

Nevirapine/Dolutegravir

Dolutegravir ↓

(Not studied, a similar reduction in exposure as observed with efavirenz is expected, due to induction)

Co-administration with nevirapine may decrease dolutegravir plasma concentration due to enzyme induction and has not been studied. Effect of nevirapine on dolutegravir exposure is likely similar to or less than that of efavirenz. The recommended dose of dolutegravir is 50 mg twice daily when co-administered with nevirapine. As Triumeq is a fixed dose tablet, an additional 50 mg tablet of dolutegravir should be administered, approximately 12 hours after Triumeq for the duration of the nevirapine co-administration (a separate preparation of dolutegravir is available for this dose adjustment, see section 4.2).

Rilpivirine

Dolutegravir ↔

AUC ↑ 12%

Cmax ↑ 13%

C ↑ 22%

Rilpivirine ↔

No dose adjustment is necessary.

Nucleoside reverse transcriptase inhibitors (NRTIs)

Tenofovir

Emtricitabine, didanosine, stavudine, zidovudine.

Dolutegravir ↔

AUC ↑ 1%

Cmax ↓ 3%

C ↓ 8%

Tenofovir ↔

Interaction not studied

No dose adjustment is necessary when Triumeq is combined with nucleoside reverse transcript inhibitors.

Triumeq is not recommended for use in combination with emtricitabine containing products, since both lamivudine (in Triumeq) and emtricitabine are cytidine analogues (i.e. risk for intracellular interactions, (see section 4.4))

Protease inhibitors

Atazanavir/Dolutegravir

Dolutegravir ↑  AUC ↑ 91%  Cmax ↑ 50%  C ↑ 180%

Atazanavir ↔ (historical controls)

(inhibition of UGT1A1 and CYP3A enzymes)

No dose adjustment is necessary.

Atazanavir+ ritonavir/ Dolutegravir

Dolutegravir ↑  AUC ↑ 62%  Cmax ↑ 34%   C ↑ 121%

Atazanavir ↔Ritonavir ↔

No dose adjustment is necessary.

Tipranavir+ritonavir/ Dolutegravir

Dolutegravir ↓  AUC ↓ 59%   Cmax ↓ 47%  C ↓ 76%

Tipranavir ↔Ritonavir ↔

(induction of UGT1A1 and CYP3A enzymes)

The recommended dose of dolutegravir is 50 mg twice daily when co-administered with tipranavir/ritonavir. As Triumeq is a fixed dose tablet, an additional 50 mg tablet of dolutegravir should be administered, approximately 12 hours after Triumeq for the duration of the tipranavir/ritonavir co-administration (a separate preparation of dolutegravir is available for this dose adjustment, see section 4.2).

Fosamprenavir+ritonavir/ Dolutegravir

Dolutegravir↓  AUC ↓ 35%   Cmax ↓ 24%   C ↓ 49%

Fosamprenavir↔

Ritonavir ↔

(induction of UGT1A1 and CYP3A enzymes)

Fosamprenavir/ritonavir decreases dolutegravir concentrations, but based on limited data, did not result in decreased efficacy in Phase III studies. No dose adjustment is necessary.

Lopinavir+ritonavir/ Dolutegravir

Lopinavir+ritonavir/ Abacavir

Dolutegravir ↔  AUC ↓ 4%  Cmax ↔ 0%   C24 ↓ 6%

Lopinavir ↔Ritonavir ↔ Abacavir AUC ↓ 32%

No dose adjustment is necessary.

Darunavir+ritonavir/ Dolutegravir

Dolutegravir ↓  AUC ↓ 22%   Cmax ↓ 11%   C ↓ 38%

Darunavir ↔Ritonavir ↔

(induction of UGT1A1 and CYP3A enzymes)

No dose adjustment is necessary.

Other antiviral agents

Daclatasvir/Dolutegravir

Dolutegravir ↔  AUC ↑ 33%   Cmax ↑ 29%  C ↑ 45%

Daclatasvir ↔

Daclatasvir did not change dolutegravir plasma concentration to a clinically relevant extent. Dolutegravir did not change daclatasvir plasma concentration. No dose adjustment is necessary.

Anti-infective products

Trimethoprim/sulfamethoxazole (Co-trimoxazole)/Abacavir

Trimethoprim/sulfamethoxazole

(Co-trimoxazole)/Lamivudine

(160mg/800mg once daily for 5 days/300mg single dose)

Interaction not studied

Lamivudine:

AUC ↑43%

Cmax ↑7%

Trimethoprim:

AUC ↔

Sulfamethoxazole:

AUC ↔

(organic cation transporter inhibition)

No Triumeq dose adjustment necessary, unless patient has renal impairment (See Section 4.2).

Antimycobacterials

Rifampicin/Dolutegravir

Dolutegravir ↓  AUC ↓ 54%  Cmax ↓ 43%  C ↓ 72%

(induction of UGT1A1 and CYP3A enzymes)

The dose of dolutegravir is 50 mg twice daily when co-administered with rifampicin. As Triumeq is a fixed dose tablet, an additional 50 mg tablet of dolutegravir should be administered, approximately 12 hours after Triumeq for the duration of the rifampicin co-administration (a separate preparation of dolutegravir is available for this dose adjustment, see section 4.2).

Rifabutin

Dolutegravir ↔  AUC ↓ 5%  Cmax ↑ 16%   C ↓ 30%

(induction of UGT1A1 and CYP3A enzymes)

No dose adjustment is necessary.

Anticonvulsants

Carbamazepine/Dolutegravir

Dolutegravir ↓  AUC ↓ 49%  Cmax ↓ 33%  C ↓ 73%

The recommended dose of dolutegravir is 50 mg twice daily when co-administered with carbamazepine. As Triumeq is a fixed dose tablet, an additional 50 mg tablet of dolutegravir should be administered, approximately 12 hours after Triumeq for the duration of the carbamazepine co-administration (a separate preparation of dolutegravir is available for this dose adjustment, see section 4.2).

Phenobarbital/Dolutegravir

Phenytoin/Dolutegravir

Oxcarbazepine/Dolutegravir

Dolutegravir↓

(Not studied, decrease expected due to induction of UGT1A1 and CYP3A enzymes, a similar reduction in exposure as observed with carbamazepine is expected)

The recommended dose of dolutegravir is 50 mg twice daily when co-administered with these metabolic inducers. As Triumeq is a fixed dose tablet, an additional 50 mg tablet of dolutegravir should be administered, approximately 12 hours after Triumeq for the duration of the co-administration with these metabolic inducers (a separate preparation of dolutegravir is available for this dose adjustment, see section 4.2).

Antihistamines (histamine H2 receptor antagonists)

Ranitidine

Interaction not studied.

Clinically significant interaction unlikely.

No dose adjustment necessary.

Cimetidine

Interaction not studied.

Clinically significant interaction unlikely.

No dose adjustment necessary.

Cytotoxics

Cladribine/Lamivudine

Interaction not studied.

In vitro lamivudine inhibits the intracellular phosphorylation of cladribine leading to a potential risk of cladribine loss of efficacy in case of combination in the clinical setting. Some clinical findings also support a possible interaction between lamivudine and cladribine

Concomitant use of Triumeq with cladribine is not recommended (see section 4.4).

Opioids

Methadone/Abacavir

(40 to 90mg once daily for 14 days/600mg single dose, then 600mg twice daily for 14 days)

Abacavir:

AUC ↔

Cmax ↓35%

Methadone:

CL/F ↑22%

Methadone dose adjustment likely not needed in majority of patients; occasionally methadone re-titration may be required.

Retinoids

Retinoid compounds (e.g. Isotretinoin)

Interaction not studied

Possible interaction given common pathway of elimination via alcohol dehydrogenase (abacavir-component).

Insufficient data to recommend dose adjustment.

Miscellaneous

Alcohol

Ethanol/Dolutegravir

Ethanol/Lamivudine

Ethanol/Abacavir

(0.7 g/kg single dose/600mg single dose)

Interaction not studied (Inhibition of alcohol dehydrogenase)

Abacavir:

AUC ↑ 41%

Ethanol:

AUC ↔

No dose adjustment necessary.

Sorbitol

Sorbitol solution (3.2 g, 10.2 g, 13.4 g)/Lamivudine

Single dose lamivudine oral solution 300 mg

Lamivudine:

AUC ↓ 14%; 32%; 36%

Cmax ↓ 28%; 52%, 55%.

When possible, avoid chronic coadministration of Triumeq with medicinal products containing sorbitol or other osmotic acting poly-alcohols or monosaccharide alcohols (eg: xylitol, mannitol, lactitol, maltitol). Consider more frequent monitoring of HIV-1 viral load when chronic coadministration cannot be avoided.

Potassium channel blockers

Fampridine (also known as dalfampridine)/Dolutegravir

Fampridine ↑

Co-administration of dolutegravir has the potential to cause seizures due to increased fampridine plasma concentration via inhibition of OCT2 transporter; co-administration has not been studied. Fampridine co-administration with Triumeq is contraindicated (see section 4.3).

Antacids and supplements

Magnesium/

aluminium‑containing antacids/Dolutegravir

Dolutegravir ↓AUC ↓ 74% Cmax ↓ 72%

(Complex binding to polyvalent ions)

Magnesium/ aluminium-containing antacids should be taken well separated in time from the administration of Triumeq (minimum 2 hours after or 6 hours before the intake of Triumeq).

Calcium supplements/Dolutegravir

Dolutegravir ↓  AUC ↓ 39%   Cmax ↓ 37%  C24 ↓ 39%

(Complex binding to polyvalent ions)

- When taken with food, Triumeq and supplements or multivitamins containing calcium, iron or magnesium can be taken at the same time.

- If Triumeq is taken in a fasted state, such supplements should be taken a minimum 2 hours after or 6 hours before the intake of Triumeq.

The stated reductions in dolutegravir exposure were observed with the intake of dolutegravir and these supplements during fasted conditions. In fed state, the changes in exposure following intake together with calcium or iron supplements were modified by the food effect, resulting in an exposure similar to that obtained with dolutegravir administered in the fasted state.

Iron supplements/Dolutegravir

Dolutegravir ↓  AUC ↓ 54%   Cmax ↓ 57%  C24 ↓ 56%

(Complex binding to polyvalent ions)

Multivitamins (containing calcium, iron and magnesium) /Dolutegravir

Dolutegravir ↓

AUC ↓ 33%

Cmax ↓ 35%

C24 ↓ 32%

Corticosteroids

Prednisone

Dolutegravir ↔

AUC ↑ 11%

Cmax ↑ 6%

C ↑ 17%

No dose adjustment is necessary.

Antidiabetics

Metformin/Dolutegravir

Metformin ↑

Dolutegravir ↔

When co-administered with dolutegravir 50mg QD:

Metformin  AUC ↑ 79%   Cmax ↑ 66%

When co-administered with dolutegravir 50mg BID:

Metformin  AUC ↑ 145 %   Cmax ↑ 111%

A dose adjustment of metformin should be considered when starting and stopping coadministration of dolutegravir with metformin, to maintain glycaemic control. In patients with moderate renal impairment a dose adjustment of metformin should be considered when coadministered with dolutegravir, because of the increased risk for lactic acidosis in patients with moderate renal impairment due to increased metformin concentration (section 4.4).

Herbal products

St. John's wort/Dolutegravir

Dolutegravir↓

(Not studied, decrease expected due to induction of UGT1A1 and CYP3A enzymes, a similar reduction in exposure as observed with carbamazepine is expected)

The recommended dose of dolutegravir is 50 mg twice daily when co-administered with St. John's wort. As Triumeq is a fixed dose tablet, an additional 50 mg tablet of dolutegravir should be administered, approximately 12 hours after Triumeq for the duration of the St John's wort co-administration (a separate preparation of dolutegravir is available for this dose adjustment, see section 4.2).

Oral contraceptives

Ethinyl estradiol (EE) and Norgestromin (NGMN)/Dolutegravir

Effect of dolutegravir:

EE ↔   AUC ↑ 3%   Cmax ↓ 1%

Effect of dolutegravir:

NGMN ↔  AUC ↓ 2%   Cmax ↓ 11%

Dolutegravir had no Pharmacodynamic effect on Luteinizing Hormone (LH), Follicle Stimulating Hormone (FSH) and progesterone. No dose adjustment of oral contraceptives is necessary when co-administered with Triumeq.

Antihypertensive

Riociguat/Abacavir

Riociguat ↑

In vitro, abacavir inhibits CYP1A1. Concomitant administration of a single dose of riociguat (0.5 mg) to HIV patients receiving Triumeq led to an approximately three-fold higher riociguat AUC(0-∞) when compared to historical riociguat AUC(0-∞) reported in healthy subjects.

Riociguat dose may need to be reduced, consult the riociguat prescribing information for dosing recommendations.

Paediatric population

Interaction studies have only been performed in adults.

4.6. Fertility, pregnancy and lactation

Pregnancy

Triumeq can be used during pregnancy if clinically needed.

A large amount of data on pregnant women (more than 1000 exposed outcomes) indicate no malformative nor feto/ neonatal toxicity associated with dolutegravir. In pregnant women treated with abacavir, a large amount of data (more than 1000 exposed outcomes) indicate no malformative nor feto/ neonatal toxicity. In pregnant women treated with lamivudine, a large amount of data (more than 1000 exposed outcomes) indicate no malformative nor feto/ neonatal toxicity.

There are no or limited amount of data (less than 300 pregnancy outcomes) on the use of this triple combination in pregnancy.

Two large birth outcome surveillance studies (over 14,000 pregnancy outcomes) in Botswana (Tsepamo) and Eswatini, and other sources, do not indicate an increased risk for neural tube defects after dolutegravir exposure.

The incidence of neural tube defects in the general population ranges from 0.5-1 case per 1,000 live births (0.05-0.1%).

Data from the Tsepamo study show no significant difference in the prevalence of neural tube defects (0.11%) in infants whose mothers were taking dolutegravir at conception (over 9,400 exposures) compared to those taking non-dolutegravir containing antiretroviral regimens at conception (0.11%), or compared to women without HIV (0.07%).

Data from the Eswatini study show the same prevalence of neural tube defects (0.08%) in infants whose mothers were taking dolutegravir at conception (over 4,800 exposures), as infants of women without HIV (0.08%).

Data analysed from the Antiretroviral Pregnancy Registry (APR) of more than 1000 pregnancies with first trimester dolutegravir treatment, more than 1000 pregnancies with first trimester abacavir treatment and over 1000 pregnancies with first trimester lamivudine treatment do not indicate an increased risk of major birth defects with dolutegravir, lamivudine or abacavir compared to the background rate or women with HIV. There are no or limited amount of APR data (less than 300 first trimester exposures) from the use of dolutegravir + lamivudine + abacavir in pregnant women..

In animal reproductive toxicology studies with dolutegravir, no adverse development outcomes, including neural tube defects, were identified (see section 5.3).

Dolutegravir crosses the placenta in humans. In pregnant women living with HIV, the median foetal umbilical cord concentration of dolutegravir was approximately 1.3-fold greater compared with the maternal peripheral plasma concentration. Placental transfer of abacavir and/or its related metabolites has been shown to occur in humans. Placental transfer of lamivudine has been shown to occur in humans.

There is insufficient information on the effects of dolutegravir on neonates.

Animal studies with abacavir have shown toxicity to the developing embryo and foetus in rats, but not in rabbits. Animal studies with lamivudine showed an increase in early embryonic deaths in rabbits but not in rats (see section 5.3).

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 (a median dolutegravir breast milk to maternal plasma ratio of 0.033 has been shown). 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 women living with HIV do not breast-feed their infants 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

Triumeq has no or negligible influence on the 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 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 reaction 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 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 list of adverse reactions associated with the combination of dolutegravir + abacavir/lamivudine in an analysis of pooled data from: Phase IIb to Phase IIIb clinical studies 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

Frequency

Adverse reaction

Blood and lymphatic systems disorders:

Uncommon:

Neutropenia1, anaemia1, thrombocytopenia1

Very rare:

pure red cell aplasia1, sideroblastic anaemia2

Immune system disorders:

Common:

hypersensitivity (see section 4.4)

Uncommon:

immune reconstitution syndrome (see section 4.4)

Metabolism and nutrition disorders:

Common:

anorexia1

Uncommon:

hypertriglyceridaemia, hyperglycaemia

Very rare:

lactic acidosis1

Psychiatric disorders:

Very common:

insomnia

Common:

abnormal dreams, depression, anxiety1, nightmare, sleep disorder

Uncommon:

suicidal ideation or suicide attempt (particularly in patients with a pre-existing history of depression or psychiatric illness), panic attack

Rare:

completed suicide (particularly in patients with a pre-existing history of depression or psychiatric illness)

Nervous system disorders:

Very common:

headache

Common:

dizziness, somnolence, lethargy1

Very rare:

peripheral neuropathy1, paraesthesia1

Respiratory, thoracic and mediastinal disorders:

Common:

cough1, nasal symptoms1

Gastrointestinal disorders:

Very common:

nausea, diarrhoea

Common:

vomiting, flatulence, abdominal pain, abdominal pain upper, abdominal distension, abdominal discomfort, gastro-oesophageal reflux disease, dyspepsia

Rare:

pancreatitis1

Hepatobiliary disorders:

Common:

alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) elevations

Uncommon:

hepatitis

Rare:

acute hepatic failure1, increased bilirubin3

Skin and subcutaneous tissue disorders:

Common:

rash, pruritus, alopecia1

Very rare:

erythema multiform1, Stevens-Johnson syndrome1, toxic epidermal necrolysis1

Musculoskeletal and connective tissue disorders:

Common:

Arthralgia1, muscle disorders1(including myalgia1)

Rare:

rhabdomyolysis1

General disorders and administration site conditions:

Very common:

fatigue

Common:

asthenia, fever1, malaise1

Investigations:

Common:

CPK elevations, weight increased

Rare:

amylase elevations1

1This adverse reaction was identified from clinical studies or post-marketing experience for dolutegravir, abacavir or lamivudine when used with other antiretrovirals or post-marketing experience with Triumeq.

2Reversible sideroblastic anaemia has been reported with dolutegravir-containing regimens. The contribution of dolutegravir in these cases is unclear.3In combination with increased transaminases.

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)

Gastrointestinal tract

Nausea, vomiting, diarrhoea, abdominal pain, mouth ulceration

Respiratory tract

Dyspnoea, cough, sore throat, adult respiratory distress syndrome, respiratory failure

Miscellaneous

Fever, lethargy, malaise, oedema, lymphadenopathy, hypotension, conjunctivitis, anaphylaxis

Neurological/Psychiatry

Headache, paraesthesia

Haematological

Lymphopenia

Liver/pancreas

Elevated liver function tests, hepatitis, hepatic failure

Musculoskeletal

Myalgia, rarely myolysis, arthralgia, elevated creatine phosphokinase

Urology

Elevated creatinine, renal failure

Symptoms related to this HSR worsen with continued therapy and can be life-threatening 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 μmol/L 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 co-infection for all treatment groups.

Paediatric population

Based on data from IMPAACT 2019 study in 57 HIV-1 infected children (aged less than 12 years and weighing at least 6 kg) who received the recommended doses of either the Triumeq film-coated tablet or dispersible tablets, there were no additional safety issues beyond those observed in the adult population.

Based on available data with dolutegravir used in combination with other antiretroviral agents to treat infants, children and adolescents, there were no additional safety related issues 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.