ViiV HEALTHCARE WELCOMES EUROPEAN COMMISSION APPROVAL OF DOLUTEGRAVIR PAEDIATRIC TYPE II VARIATION AND EXTENSION APPLICATIONS

ViiV Healthcare has today announced that the European Commission has approved the Type II variation and extension applications to reduce the weight and age limit for the treatment of HIV in children and adolescents with Tivicay ( dolutegravir ) from at least 40kg to at least 15kg, in ages six to less than 12 years old, and to register new dose strengths of 10mg and 25mg oral tablets.[1]

This approval follows the Committee for Medicinal Products for Human Use (CHMP) positive opinion in December 2016 and the U.S. Food and Drug Administration’s (FDA) paediatric approval, in June 2016, of dolutegravir for a reduced age and weight limit.

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Note to editors

About HIV

HIV stands for the Human Immunodeficiency Virus. Unlike some other viruses, the human body cannot get rid of HIV, so once someone has HIV they have it for life. There is no cure for HIV, but effective treatment can control the virus so that people with HIV can enjoy healthy and productive lives.  

About Tivicay® ( dolutegravir )

Dolutegravir (Tivicay) is an integrase strand transfer inhibitor (INSTI) for use in combination with other antiretroviral agents for the treatment of HIV. Integrase inhibitors block HIV replication by preventing the viral DNA from integrating into the genetic material of human immune cells (T-cells). This step is essential in the HIV replication cycle and is also responsible for establishing chronic infection. Tivicay is approved in over 100 countries across North America, Europe, Asia, Australia, Africa and Latin America.

Important information about Tivicay® ( dolutegravir ) (based on dolutegravir SmPC from EMA):

EMA indications and usage: Tivicay is indicated in combination with other antiretroviral medicinal products for the treatment of Human Immunodeficiency Virus (HIV) infected adults, adolescents and children above 6 years of age.

Use of Tivicay 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 two active agents) due to advanced multiclass resistance .The decision to use dolutegravir for such patients should be informed by the integrase resistance pattern. Co-administration of Tivicay with some medicines should be avoided in this population (e.g. efavirenz, nevirapine, tipranavir/ritonavir or rifampicin).

Contraindications:

Tivicay is contraindicated in patients:

• With previous hypersensitivity reaction to dolutegravir
• Receiving dofetilide (antiarrhythmic)

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 characterised 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) 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 antiepileptic drugs).

Dolutegravir increased metformin concentrations: a dose adjustment of metformin should be considered when starting and stopping co-administration 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 of 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.

Adverse reactions: 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%).

Pregnancy: Dolutegravir should be used during pregnancy only if the expected benefit justifies the potential risk to the foetus .

Breastfeeding: It is recommended that HIV-infected women do not breastfeed their infants under any circumstances in order to avoid transmission of HIV.

The full EU SmPC for Tivicay® ( dolutegravir ) is available here.

References

[1] ViiV Healthcare - Tivicay® Summary of Product Characteristics, updated February 2017