Triumeq

/ GSK

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

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

Hypersensitivity to dolutegravir, abacavir or lamivudine or to any of the excipients. Co-administration with dofetilide.

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: Both abacavir and dolutegravir are associated with a risk for hypersensitivity reactions (HSR), 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 This formulation 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.
– This formulation 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.
– This product 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 this product 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 this product for reasons of a suspected HSR, this formulatin 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 tablets of this product.
See prescribing information for full details.
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 this formulatin has not been established in patients with significant underlying liver disorders. This product is not recommended in patients with moderate to severe hepatic impairment.
See prescribing information for full details.
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.
See prescribing information for full details.
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 evaluated and treatment instituted when necessary. Autoimmune disorders (such as Graves’ disease) have also been reported to occur in the setting of immune reactivation.
See prescribing information for full details.
Mitochondrial dysfunction: Nucleoside and nucleotide analogues have been demonstrated in vitro and in vivo to cause a variable degree of mitochondrial damage.
See prescribing information for full details.
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.
See prescribing information for full details.
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 this product 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 this product is not recommended for patients with integrase inhibitor resistance.
See prescribing information for full details.

Immune system disorders: Common: hypersensitivity.
Metabolism and nutrition disorders: Common: anorexia.
Psychiatric disorders: Very common: insomnia. Common: abnormal dreams, depression, anxiety, nightmare, sleep disorder.
Nervous system disorders: Very common: headache. Common: dizziness, somnolence, lethargy.
Respiratory, thoracic and mediastinal disorders: Common: cough, nasal symptoms.
Gastrointestinal disorders: Very common: nausea, diarrhoea. Common: vomiting, flatulence, abdominal pain, abdominal pain upper,
abdominal distension, abdominal discomfort, gastrooesophageal reflux disease, dyspepsia.
Skin and subcutaneous tissue disorders: Common: rash, pruritus, alopecia.
Musculoskeletal and connective tissue disorders: Common: arthralgia, muscle disorders.
General disorders and administration site conditions: Very common: fatigue. Common: asthenia, fever, malaise.
Investigations: Common: CPK elevations2, ALT/AST elevations.
See prescribing information for full details.

This product contains dolutegravir, abacavir and lamivudine, therefore any interactions identified for these individually are relevant to this formulation. 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 this product 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. The absorption of dolutegravir is reduced by certain anti-acid agents. 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 MATE2-K). 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 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. 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).
Since the recommended dose of dolutegravir is 50 mg twice daily when co-administered with etravirine (without boosted protease inhibitors, efavirenz, nevirapine, rifampicin, tipranavir/ritonavir, carbamazepine, phenytoin, phenobarbital and St. John’s wort, the use of This product is not recommended for patients taking these medicines.
This product should not be co-administered with polyvalent cation-containing antacids. This product is recommended to be administered 2 hours before or 6 hours after these agents. This product is recommended to be administered 2 hours before or 6 hours after taking calcium or iron supplements. 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. 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. This formulation should not be taken with any other medicinal products containing dolutegravir, abacavir, lamivudine or emtricitabine.
See prescribing information for full details.  

Pregnancy: As a general rule, when deciding to use antiretroviral agents for the treatment of HIV infection in pregnant women and consequently for reducing the risk of HIV vertical transmission to the newborn, the animal data as well as the clinical experience in pregnant women should be taken into account.
See prescribing information for full details.
Lactation: It is unknown whether dolutegravir is excreted in human milk. Abacavir is 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.
See prescribing information for full details.

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 this product. 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.

Storage: Do not store above 30°C. Store in the original package in order to protect from moisture. Keep the bottle tightly closed. Do not remove the desiccant. Use within 30 days after opening.