Swiss Summary of the Risk Management Plan (RMP) for

Transcription

1 Swiss Summary of the Risk Management Plan (RMP) for GENVOYA (Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Alafenamide) Version 2.0 (July 2017) Gilead Sciences International Limited Granta Park, Abington Cambridge CB21 6GT United Kingdom

2 The Risk Management Plan (RMP) is a comprehensive document submitted as part of the application dossier for market approval of a medicine. The RMP summary contains information on the medicine's safety profile and explains the measures that are taken in order to further investigate and follow the risks as well as to prevent or minimize them. The RMP summary of Genvoya is a concise document and does not claim to be exhaustive. As the RMP is an international document, the summary might differ from the Arzneimittelinformation approved and published in Switzerland, e.g. by mentioning risks occurring in populations or indications not included in the Swiss authorization. Please note that the reference document which is valid and relevant for the effective and safe use of Genvoya in Switzerland is the Arzneimittelinformation (see approved and authorized by Swissmedic. Gilead Sciences International Limited is fully responsible for the accuracy and correctness of the content of the here published summary RMP of Genvoya. Overview of disease epidemiology Human immunodeficiency virus (HIV) (is a virus that attacks the immune system and weakens the body s ability to fight infections and disease. A person with HIV infection is considered to have developed acquired immune deficiency syndrome (AIDS) when the immune system is so weak it can no longer fight off a range of diseases with which it would normally cope. In 2012, over 35 million people were living with HIV, increased from 34 million in 2011 (including 860,000 in Western and Central Europe and 1.3 million in Eastern Europe and Central Asia). In 2012, about 2.3 million people were newly infected with HIV. In 2012, 1.6 million people died of AIDS, including 7,600 in Western and Central Europe and 91,000 in Eastern Europe and Central Asia. HIV infection remains a life-threatening disease in infected persons who do not receive adequate treatment. The number of people dying from causes related to AIDS has declined because of an increase in the availability of treatments for HIV. Most people who die from AIDS are from sub-saharan Africa. Summary of treatment benefits Genvoya is a treatment for adults and adolescents (aged 12 years and over with body weight at least 35 kg) with human immunodeficiency virus (HIV) infection that is not resistant to any of the medicines in Genvoya. Genvoya contains 4 active drugs, elvitegravir (EVG), an antiretroviral medicine known as an integrase inhibitor, cobicistat (COBI), a booster (pharmacokinetic enhancer) of the effects of EVG, emtricitabine (FTC), an antiretroviral medicine known as a nucleoside reverse transcriptase inhibitor, and tenofovir alafenamide (TAF), an antiretroviral medicine known as a nucleotide reverse transcriptase inhibitor. Genvoya reduces the amount of HIV in the body. This improves the body s immune system and reduces the risk of developing illnesses linked to HIV infection. Results from the 2 main studies for Genvoya in 1733 patients aged between 18 to 76 years, showed that Genvoya was as effective in treating HIV infection as Stribild, another medicine containing several drugs to treat HIV infection. A separate study showed that Genvoya was effective in treating HIV infection in adolescent patients aged 12 to 17 years.

3 Unknowns relating to treatment benefits Development of drug resistance during 2 years of treatment with Genvoya was rare. There is currently limited information with more prolonged use of Genvoya. In addition, no or limited information on the effectiveness of Genvoya in treating HIV infection is currently available in the following patient populations: pregnant women, breastfeeding women, patients with severely decreased renal function (estimated creatinine clearance less than 30 ml/min), patients with severely decreased liver function, patients with heart rhythm problems, and patients infected with both HIV and hepatitis C virus(hcv). There is no evidence to suggest that the effectiveness of Genvoya would be any different in these patient populations compared to that observed in the main Genvoya studies. Summary of safety concerns Important identified risks Risk What is known Preventability Liver problems (flare-up of hepatitis) in patients infected with both HIV-1 and hepatitis B virus (HBV) who stop treatment with Genvoya The FTC and TAF components of Genvoya have anti-hbv activity as well as being anti-hiv drugs. Stopping Genvoya in patients who also have HBV infection may lead to worsening of liver problems (flare-up of hepatitis). Yes, by not stopping Genvoya treatment without talking to a doctor first, by initiating anti-hbv therapy if Genvoya is stopped or by closely monitoring the patient for worsening of liver problems if treatment is stopped. Important potential risks Risk Suicidal ideation and suicide attempt in patients who have had depression or mental health problems before starting Genvoya What is known There is currently not enough evidence to support Genvoya causing patients to have suicidal thoughts or suicide attempts. Other anti-hiv drugs that contain EVG have been associated with a slightly higher rate of suicidal thoughts or suicide attempt compared to some other anti-hiv drugs. Kidney problems Genvoya contains tenofovir. Another drug that contains a different form of tenofovir, tenofovir disoproxil fumarate (TDF), has been associated with renal toxicity, which is thought to be due to damage to kidney tubule cells. Levels of tenofovir in the blood are more than 90% lower with Genvoya compared with drugs that contain TDF. Clinical trial data indicate that Genvoya has little or no effect on the function of the kidney tubule cells (including in patients with mildly or moderately decreased renal function) compared to a worsening for products containing TDF. The data also suggest an improvement in the function of kidney tubule cells on switching from medicines that contain TDF to Genvoya. No patients treated with Genvoya had damage to kidney tubule cells in clinical studies. Therefore, the potential risk of kidney problems is considered to be very low for Genvoya.

4 Risk Bone problems What is known Damage to kidney tubule cells associated with products that contain TDF can cause bone softening (with bone pain and sometimes resulting in fractures). As described above, no patients treated with Genvoya had damage to kidney tubule cells in clinical studies. Thinning of bones (decrease in bone mineral density [BMD]) has been observed in patients after starting treatment with anti-hiv drugs, with the largest decreases in BMD with products that contain TDF. Decreases in BMD after starting Genvoya were similar to those seen after the start of treatment with other anti-hiv drugs that do not contain TDF. Moreover, increases in BMD were observed upon switching from products that contain TDF to Genvoya in 2 separate studies. Eye effects (inflammation at the back of the eye) Inflammation at the back of the eye was present in some dogs administered high doses of the TAF component of Genvoya. This finding did not occur in animals given lower doses or in other animal studies, and there have been no reports of this in human clinical studies. Use of medicines that should never be taken with Genvoya The following drugs should never be taken with Genvoya as the levels of these drugs may increase significantly in blood potentially causing serious side effects: alfuzosin amiodarone, quinidine dihydroergotamine, ergometrine, ergotamine cisapride lovastatin, simvastatin pimozide sildenafil for the treatment of pulmonary arterial hypertension orally administered midazolam, triazolam The following drugs should never be taken with Genvoya as they may lower the levels of COBI and EVG in the blood which could result EVG not being effective and development of resistance to EVG: carbamazepine, phenobarbital, phenytoin rifampicin Herbal products: St John s wort (Hypericum perforatum) Overdose of tenofovir through accidental use of Genvoya with a medicine containing tenofovir disoproxil fumarate Taking medicines containing TDF results in high levels of tenofovir in the blood, which can cause kidney problems. Taking Genvoya with a medicine containing TDF is expected to have little effect on the amount of tenofovir in the blood compared to taking TDF alone.

5 Missing information Risk Limited information on longterm use of Genvoya in adults and adolescents with HIV-1 infection children aged 6 to < 12 years pregnant women and breastfeeding women What is known Genvoya was well tolerated in clinical studies in adults over 1 to 3 years and in adolescents over 1 year. Clinical studies are ongoing to provide further information on long-term safety of Genvoya. Genvoya is not recommended for use in children below 12 years of age due to a lack of data on safety and efficacy, and the inability to adjust dose or dose interval. Emtriva (FTC) is approved for use in HIV-1 infected infants, children, and adolescents (aged 4 months and above). Genvoya has not been studied in pregnant women. A large amount of information has been received on pregnant women using FTC that has shown no harmful effects on the unborn child. Genvoya should not be used during pregnancy unless the patient and the patient s doctor decide it is clearly needed. Emtricitabine has been shown to pass into human breast milk. It is not known whether EVG, COBI or TAF pass into human breast milk. It is recommended that mothers with HIV infection do not breastfeed their infants as HIV may be carried through the breast milk to the infant during nursing. patients with severely decreased renal function patients with severely decreased liver function Genvoya was well tolerated in patients with mildly or moderately decreased renal function, with a safety profile similar to that in patients with normal renal function. Genvoya has not been studied in patients with severely decreased renal function (estimated creatinine clearance less than 30 ml/min). The EVG, COBI and TAF components of Genvoya have not been studied in patients with severely decreased liver function. No change in the dose of EVG, COBI and TAF is required in patients with mildly or moderately decreased liver function. patients with heart rhythm problems patients infected with HIV and hepatitis C virus Clinical studies of medicines containing COBI, including Genvoya, have not shown a risk of heart problems associated with COBI. Cobicistat has not been studied in patients who had significant heart rhythm related problems before starting the study. No data are currently available for Genvoya in HIV-infected patients who also have HCV infection. Limited information on drug resistance with long-term use of Genvoya Development of drug resistance during 2 years of treatment with Genvoya was rare. Limited information on drugdrug interactions When given together, Genvoya has the potential to affect the blood levels of some other drugs and other drugs may affect the blood levels of some of the components of Genvoya.

6 Summary of risk minimisation measures by safety concern All medicines have a Summary of Product Characteristics (SmPC) which provides physicians, pharmacists and other healthcare professionals with details on how to use the medicine, the risks and recommendations for minimising them. An abbreviated version of this in lay language is provided in the form of the package leaflet ( Patienteninformation ). The measures in these documents are known as routine risk minimisation measures. The current Information for Professionals and the Patient Information for Genvoya can be found on Genvoya has no additional risk minimization measures. Planned post-authorisation development plan List of studies in post-authorisation development plan Study/Activity (Including Study Number) Objectives Safety Concerns/Efficacy Issues Addressed Status Planned Date for Submission of (Interim and) Final Results Study GS-US (Interventional clinical study) To evaluate the safety of Genvoya versus another anti-hiv medicine, Stribild in adults with HIV infection who have not previously been treated with anti-hiv medicines Important potential risk: Suicidal ideation and suicide attempt in patients who have had depression or mental health problems before starting Genvoya Long-term use of Genvoya Started Q (3 year report) Study GS-US (Interventional clinical study) To evaluate the safety of Genvoya versus another anti-hiv medicine, Stribild in adults with HIV infection who have not previously been treated with anti-hiv medicines Important potential risk: Suicidal ideation and suicide attempt in patients who have had depression or mental health problems before starting Genvoya Long-term use of Genvoya Started Q (3 year report)

7 Study/Activity (Including Study Number) Objectives Safety Concerns/Efficacy Issues Addressed Status Planned Date for Submission of (Interim and) Final Results Antiretroviral Pregnancy Registry (Observational study) To collect information on the risk of birth defects in patients exposed to anti- HIV medicines, including the components of Genvoya, during pregnancy Use in pregnant women Started Interim reports to be included in Genvoya periodic safety update reports (PSURs) In vitro study on the potential for significant effects on plasma tenofovir concentrations upon coadministration of tenofovir alafenamide and xanthine oxidase inhibitors To provide information on the potential for a drug-drug interaction between Genvoya and xanthine oxidase inhibitors Drug-drug interactions Started Q (final report) Studies which are a condition of the marketing authorisation None of the above studies are a condition of the marketing authorisation. Summary of changes to the risk management plan over time Changes to the Risk Management Plan over time Version Date Safety Concerns Comment(s) December 2015 Lipoatrophy removed as an important potential risk. The benefit-risk profile of Genvoya continues to be positive November 2016 Relevant 2-year data from Study GS-US in patient with mildly or moderately decreased renal function added to RMP. No new safety concerns were identified from these data. The indication for Genvoya was extended to include pediatric patients aged 6 years or older, weighing at least 25 kg. The benefit-risk profile of Genvoya continues to be positive. This summary was last updated in