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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.
Integrase class resistance of particular concern: The decision to use dolutegravir in the presence of integrase class resistance should take into account that the activity of dolutegravir is considerably compromised for viral strains harbouring Q148+≥2 secondary mutations from G140A/C/S, E138A/K/T, L74I (see Pharmacology: Pharmacodynamics under Actions). To what extent dolutegravir provides added efficacy in the presence of such integrase class resistance is uncertain (see Pharmacology: Pharmacokinetics under Actions).
Hypersensitivity reactions: Hypersensitivity reactions have been reported with dolutegravir, and were characterized by rash, constitutional findings, and sometimes, organ dysfunction, including severe liver reactions. Dolutegravir and other suspect agents should be discontinued immediately if signs or symptoms of hypersensitivity reactions develop (including, but not limited to, severe rash or rash accompanied by raised liver enzymes, fever, general malaise, fatigue, muscle or joint aches, blisters, oral lesions, conjunctivitis, facial oedema, eosinophilia, angioedema). Clinical status including liver aminotransferases and bilirubin should be monitored. Delay in stopping treatment with dolutegravir or other suspect active substances after the onset of hypersensitivity may result in a life-threatening allergic reaction.
Patients co-infected with HIV and hepatitis B or C virus: Patients with chronic hepatitis B or C treated with antiretroviral therapy are at an increased risk for severe and potentially fatal hepatic adverse reactions.
The safety and efficacy of Dolutegravir, Emtricitabine and Tenofovir alafenamide in patients co-infected with HIV-1 and hepatitis C virus (HCV) have not been established. Tenofovir alafenamide is active against hepatitis B virus (HBV), but its clinical efficacy against this virus is under investigation and is not yet fully established.
Discontinuation of Dolutegravir, Emtricitabine and Tenofovir alafenamide therapy in patients co-infected with HIV and HBV may be associated with severe acute exacerbations of hepatitis. Patients co-infected with HIV and HBV who discontinue Dolutegravir, Emtricitabine and Tenofovir alafenamide should be closely monitored with both clinical and laboratory follow-up for at least several months after stopping treatment.
Dolutegravir, Emtricitabine and Tenofovir alafenamide should not be administered concomitantly with medicinal products containing tenofovir disoproxil (as fumarate), lamivudine or adefovir dipivoxil used for the treatment of HBV infection.
Liver disease: The safety and efficacy of Dolutegravir, Emtricitabine and Tenofovir alafenamide in patients with significant underlying liver disorders have not been established (see Dosage & Administration and Pharmacology: Pharmacokinetics under Actions).
Patients with pre-existing liver dysfunction, including chronic active hepatitis, have an increased frequency of liver function abnormalities during combination antiretroviral therapy (CART) 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.
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.
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 postnatally to nucleoside analogues. The main adverse reactions reported are haematological disorders (anaemia, neutropenia), metabolic disorders (hyperlactataemia, hyperlipasaemia). These events 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.
Immune Reactivation Syndrome: In HIV infected patients treated with CART, immune reactivation syndrome has been reported. In HIV infected patients with severe immune deficiency at the time of institution of 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 include cytomegalovirus retinitis, generalized and/or focal mycobacterial infections, and Pneumocystis jirovecii 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; however, the reported time to onset is more variable, and these events can occur many months after initiation of treatment.
Liver biochemistry 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 biochemistries is recommended in patients with hepatitis B and/or C co-infection. Particular diligence should be applied in initiating or maintaining effective hepatitis B therapy (referring to treatment guidelines) when starting dolutegravir-based therapy in hepatitis B co-infected patients (see Adverse Reactions).
Patients with HIV-1 harbouring mutations: Dolutegravir, Emtricitabine and Tenofovir alafenamide should be avoided in antiretroviral-experienced patients with HIV-1 harbouring the K65R mutation (see Pharmacology: Pharmacodynamics under Actions).
Triple nucleoside therapy: There have been reports of a high rate of virological failure and of emergence of resistance at an early stage when tenofovir disoproxil fumarate was combined with lamivudine and abacavir as well as with lamivudine and didanosine as a once daily regimen.
Opportunistic infections: Patients receiving Dolutegravir, Emtricitabine and Tenofovir alafenamide or any other antiretroviral therapy may continue to develop opportunistic infections and other complications of HIV infection, and, therefore, should remain under close clinical observation by physicians experienced in the treatment of patients with HIV associated diseases.
Drug interactions: Factors that decrease dolutegravir exposure should be avoided. This includes co-administration with medicinal products that reduce dolutegravir exposure (e.g., magnesium/ aluminium-containing antacid, iron and calcium supplements, multivitamins and inducing agents, etravirine (without boosted protease inhibitors), tipranavir/ritonavir, rifampicin, St. John's wort and certain antiepileptic drugs) (see Interactions).
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 Interactions). 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.
Osteonecrosis: Although the etiology is considered to be multifactorial (including corticosteroid use, 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.
Nephrotoxicity: A potential risk of nephrotoxicity resulting from chronic exposure to low levels of tenofovir due to dosing with tenofovir alafenamide cannot be excluded (see Pharmacology: Toxicology: Preclinical safety data under Actions).
Excipients: Dolutegravir, Emtricitabine and Tenofovir alafenamide tablets contains 120.00 mg of lactose monohydrate. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
Co-administration of other medicinal products: The co-administration of Dolutegravir, Emtricitabine and Tenofovir alafenamide is not recommended with certain anticonvulsants (e.g., carbamazepine, oxcarbazepine, phenobarbital and phenytoin), antimycobacterials (e.g., rifampicin, rifabutin, rifapentine), boceprevir, telaprevir, St. John's wort and HIV protease inhibitors (PIs) other than atazanavir, lopinavir and darunavir (see Interactions).
Dolutegravir, Emtricitabine and Tenofovir alafenamide should not be administered concomitantly with medicinal products containing tenofovir disoproxil (as fumarate), emtricitabine, lamivudine or adefovir dipivoxil.
Effects on ability to drive and use machines: Patients should be informed that dizziness has been reported during treatment with Dolutegravir, Emtricitabine and Tenofovir alafenamide. The clinical status of the patient and the adverse reaction profile should be borne in mind when considering the patient's ability to drive or operate machinery.
Use in Pregnancy: Embryo-Fatal Toxicity: Preliminary data from an observation study showed that dolutegravir was associated with increased risk of neural tube defects when administered at the time of conception and in early pregnancy. As there is limited understanding of reported types of neural tube defects associated with dolutegravir use and because the date of conception may not be determined with precision, avoid use of dolutegravir at the time of conception through the first trimester of pregnancy.
If there are plans to become pregnant or if pregnancy is confirmed within the first trimester while on dolutegravir, if possible, switch to an alternative regimen.
Perform pregnancy testing before initiation of dolutegravir in adolescents and adults of childbearing potential to exclude use of dolutegravir during the first trimester of pregnancy.
Advise adolescents and adults of childbearing potential to consistently use effective contraception.
