Tivicay

/ GSK

Tivicay should be prescribed by physicians experienced in the management of HIV infection.
Adults:
Patients infected with HIV-1 without documented or clinically suspected resistance to the integrase class: The recommended dose of dolutegravir is 50 mg (one tablet) orally once daily.
Dolutegravir should be administered twice daily in this population when co-administered with some medicines (e.g. efavirenz, nevirapine, tipranavir/ritonavir, or rifampicin).
Patients infected with HIV-1 with resistance to the integrase class (documented or clinically suspected): The recommended dose of dolutegravir is 50 mg (one tablet) twice daily.
In the presence of documented resistance that includes Q148 + ≥2 secondary mutations from G140A/C/S, E138A/K/T, L74I, modelling suggests that an increased dose may be considered for patients with limited treatment options (less than 2 active agents) due to advanced multi class resistance.
The decision to use dolutegravir for such patients should be informed by the integrase resistance pattern.
Adolescents aged 12 and above: In adolescents (12 to less than 18 years of age and weighing at least 40 kg) infected with HIV-1 without resistance to the integrase class, the recommended dose of dolutegravir is 50 mg once daily. In the presence of integrase inhibitor resistance, there are insufficient data to recommend a dose for dolutegravir in adolescents.
Children 6 to less than 12 years of age: In patients infected with HIV-1 without resistance to the integrase class, the recommended dose of dolutegravir in children (6 to less than 12 years of age and weighing at least 15 kg) is determined according to the weight of the child. In the presence of integrase inhibitor resistance, there are insufficient data to recommend a dose for dolutegravir in children. Dose recommendations according to weight are presented below:
Body weight (kg):
15 to less than 20: 20 mg once daily (Taken as two 10 mg tablets)
20 to less than 30: 25 mg once daily
30 to less than 40: 35 mg once daily (Taken as one 25 mg and one 10 mg tablet)
40 or greater 50 mg: once daily
The specific dosage recommendation for the 10 mg tablet, as specified above, should be followed. Therefore, the 50 mg once daily dose should not be given as five 10 mg tablets .
Missed doses: If the patient misses a dose of Tivicay, the patient should take Tivicay 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 in patients aged 65 years and over. There is no evidence that elderly patients require a different dose than younger adult patients.
Renal impairment: No dosage adjustment is required in patients with mild, moderate or severe (CrCl <30mL/min, not on dialysis) renal impairment. No data are available in subjects receiving dialysis although differences in pharmacokinetics are not expected in this population.
Hepatic impairment: No dosage adjustment is required in patients with mild or moderate hepatic impairment (Child-Pugh grade A or B). No data are available in patients with severe hepatic impairment (Child-Pugh grade C); therefore dolutegravir should be used with caution in these patients.
Paediatric population: The safety and efficacy of dolutegravir in children aged less than 6 years or weighing less than 15 kg have not yet been established. In the presence of integrase inhibitor resistance, there are insufficient data to recommend a dose for dolutegravir in children and adolescents.
Method of administration: Oral use. Tivicay can be taken with or without food. In the presence of integrase class resistance, Tivicay should preferably be taken with food to enhance exposure (particularly in patients with Q148 mutations).

Tivicay is indicated in combination with other anti-retroviral medicinal products for the treatment of Human Immunodeficiency Virus (HIV) infected adults, adolescents and children above 6 years of age.

Hypersensitivity to the active substance or to any of the excipients. Co-administration with dofetilide.

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. To what extent dolutegravir provides added efficacy in the presence of such integrase class resistance is uncertain.
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.
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. 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 reconstitution, 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
Opportunistic infections: Patients should be advised that dolutegravir 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 interactions: Factors that decrease dolutegravir exposure should be avoided in the presence of integrase class resistance. 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 anti-epileptic drugs).
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
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 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.
Lamivudine and dolutegravir: The two-drug regimen of dolutegravir 50 mg once daily and lamivudine 300 mg once daily was explored in two large randomized and blinded studies, GEMINI 1 and GEMINI 2. This regimen is only suitable for the treatment of HIV-1 infection where there is no known or suspected resistance to the integrase inhibitor class, or to lamivudine.

The most severe adverse reaction, seen in an individual patient, was a hypersensitivity reaction that included rash and severe liver effects. The most commonly seen treatment emergent adverse reactions were nausea (13%), diarrhoea (18%) and headache (13%).
See prescribing information for full details.

Effect of other agents on the pharmacokinetics of dolutegravir: All factors that decrease dolutegravir exposure should be avoided in the presence of integrase class resistance.
Dolutegravir is eliminated mainly through metabolism by UGT1A1. Dolutegravir is also a substrate of UGT1A3, UGT1A9, CYP3A4, Pgp, and BCRP; therefore medicinal products that induce those enzymes may decrease dolutegravir plasma concentration and reduce the therapeutic effect of dolutegravir. Co-administration of dolutegravir and other medicinal products that inhibit these enzymes may increase dolutegravir plasma concentration.
The absorption of dolutegravir is reduced by certain anti-acid agents.
Effect of dolutegravir 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 organic cation transporter 2 (OCT2) and multidrug and toxin extrusion transporter (MATE) 1. 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).
In vitro, dolutegravir inhibited the renal uptake transporters, organic anion transporters (OAT1) 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.
See prescribing information for full details.

Pregnancy: There are limited amount of data from the use of dolutegravir in pregnant women. The effect of dolutegravir on human pregnancy is unknown. In reproductive toxicity studies in animals, dolutegravir was shown to cross the placenta. Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity. Dolutegravir should be used during pregnancy only if the expected benefit justifies the potential risk to the foetus.
Breast-feeding: It is unknown whether dolutegravir is excreted in human milk. Available toxicological data in animals has shown excretion of dolutegravir in milk. In lactating rats that received a single oral dose of 50 mg/kg at 10 days postpartum, dolutegravir was detected in milk at concentrations typically higher than blood. It is recommended that HIV infected women do not breast-feed their infants under any circumstances in order to avoid transmission of HIV.

There is currently limited experience with overdosage in dolutegravir.
Limited experience of single higher doses (up to 250 mg in healthy subjects) revealed no specific symptoms or signs, 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 dolutegravir. If overdose occurs, the patient should be treated supportively with appropriate monitoring, as necessary. 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.