ViiV Healthcare Announces CHMP positive opinion to lower the age and weight limit for Tivicay® (dolutegravir) in children and adolescents living with HIV in Europe
ViiV Healthcare today announced that the Committee for Medicinal Products for Human Use (CHMP) has adopted a positive opinion on 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.
Following today’s positive opinion and a subsequent final amendment of the marketing authorisation by the European Medicines Authority (EMA), more children and adolescents will be eligible to receive dolutegravir in the 28 European Union member states, plus Iceland, Norway and Liechtenstein. The variation indicates the recommended dose for children from six to less than 12 years of age is to be determined according to the weight of the child, ranging from a 20mg once-daily dose for children weighing between 15kg and 20kg to a 50mg once-daily dose for children weighing 40kg or greater. This weight band-determined dosing reflects the World Health Organization (WHO) guidelines on antiretroviral therapy for HIV infection in infants and children.
“Young people living with HIV face a lifetime of managing a challenging chronic condition. Currently, they have a limited range of therapeutic options available, making any new treatment options licensed for this patient population particularly important,” said John C. Pottage, Jr., MD, Chief Scientific and Medical Officer, ViiV Healthcare. “Through our research and development efforts, we are committed to further investigating the potential of dolutegravir in younger age-groups and fulfil our promise to leave no patient behind.”
This positive opinion is based on 24-week data from the Phase I/II multi-centre, open-label, P1093 study conducted in collaboration with the International Maternal Pediatric Adolescent AIDS Clinical Trial (IMPAACT) Network. IMPAACT P1093 is an ongoing, pharmacokinetic (PK), safety and efficacy study of dolutegravir plus optimised background regimen (OBR) in children and adolescents infected with HIV-1 in age-defined cohorts.
Results from the study show that treatment with dolutegravir plus OBR was generally well-tolerated and provided efficacy through to week 24 in HIV-infected children and adolescents from six to 12 years of age weighing at least 30kg. The adverse event (AE) profile in the study was similar to that for adults. Grade 2 AEs reported by more than one patient were decreased neutrophil count (n = 3) and diarrhoea (n = 2). There were no Grade 3 or 4 drug-related AEs reported, and no AEs led to discontinuation.
An integral part of ViiV Healthcare’s access efforts is to ensure dolutegravir is available to people living with HIV and we make every effort to file for regulatory approvals of dolutegravir in all parts of the world, understanding that such approvals are subject to local review. This CHMP positive opinion follows the U.S. Food and Drug Administration’s (FDA) paediatric approval in June 2016, of dolutegravir for a reduced age and weight limit.
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 infection, but effective treatment can control the virus so that people with HIV can enjoy healthy and productive lives.
About the P1093 IMPAACT study
P1093 is a Phase I/II, multi-centre, open-label, non-comparative intensive pharmacokinetic and safety study of dolutegravir in combination regimens in HIV-1 infected infants, children and adolescents. The primary objectives of the study are to select a dolutegravir dose for chronic dosing; to determine the safety and tolerability of the dose, to evaluate the steady-state pharmacokinetics of dolutegravir in combination with other antiretrovirals and to determine the dose of dolutegravir that achieves a targeted AUC24 (primary PK endpoint) and C24h (secondary PK endpoint) in children and adolescents.3
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.
Tivicay is a registered trademark of the ViiV Healthcare group of companies.
Important Information about Tivicay® (dolutegravir) (based on approved dolutegravir adult Europe SmPC):
EMA Indications and Usage: Tivicay is indicated in combination with other anti-retroviral medicinal products for the treatment of Human Immunodeficiency Virus (HIV) infected adults and adolescents above 12 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 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. Co-administration of Tivicay with some medicines should be avoided in this population (e.g. efavirenz, nevirapine, tipranavir/ritonavir, or rifampicin).
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 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.
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.
Breast feeding: It is recommended that HIV-infected women do not breast-feed their infants under any circumstances in order to avoid transmission of HIV.
The full EU SmPC for Tivicay® (dolutegravir) is available here.
About ViiV Healthcare
ViiV Healthcare is a global specialist HIV company established in November 2009 by GlaxoSmithKline (LSE: GSK) and Pfizer (NYSE: PFE) dedicated to delivering advances in treatment and care for people living with HIV and for people who are at risk of becoming infected with HIV. Shionogi joined in October 2012. The company’s aim is to take a deeper and broader interest in HIV/AIDS than any company has done before and take a new approach to deliver effective and innovative medicines for HIV treatment and prevention, as well as support communities affected by HIV. For more information on the company, its management, portfolio, pipeline, and commitment, please visit www.viivhealthcare.com.
Summary of CHMP opinion: http://www.ema.europa.eu/docs/en_GB/document_library/Summary_of_opinion/human/002753/WC500218158.pdf . Last accessed December 2016
 World Health Organization. HIV/AIDS Programme. Antiretroviral therapy for HIV infection in infants and children: towards universal access. 2010 revision.
 IMPAACT P1093 Study Protocol Final Version 4.0 13 April 2016. Available at: http://impaactnetwork.org/studies/P1093.asp. Last accessed December 2016
 IMPAACT. P1093 (DAIDS ID 11773): Phase I/II, Multi-Center, Open-Label, Pharmacokinetic Safety, Tolerability and Antiviral Activity of GSK1349572, a Novel Integrase Inhibitor, in Combination Regimens in HIV-1 Infected Infants, Children and Adolescents. Available at: http://impaactnetwork.org/studies/P1093.asp Last accessed: December 2016
 ViiV Healthcare announces FDA approval to lower the weight limit for dolutegravir in children and adolescents living with HIV. Available at: https://www.viivhealthcare.com/media/press-releases/2016/june/viiv-healthcare-announces-fda-approval-to-lower-the-weight-limit-for-dolutegravir-in-children-and-adolescents-living-with-hiv.aspx. Last accessed December 2016
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