Risk Management Plan Emtricitabine/Tenofovir disoproxil RMP Version 3.0
Safety concern Routine risk minimisation measures Additional risk minimisation measures
measures including the prescription only status of the product.
Missing information: Section 4.2, 4.4, 4.8 and 5.2 of None proposed Safety in patients with Accord’s Emtricitabine/Tenofovir renal impairment disoproxil SmPC and corresponding section of PIL have information on this safety concern.
Other routine risk minimisation measures including the prescription only status of the product.
VI.2 Elements for a public summary
VI.2.1 Overview of disease epidemiology
HIV (viral infection):
HIV stands for human immunodeficiency virus. It kills or damages the body's immune system cells. AIDS (acquired immunodeficiency syndrome) is the most advanced stage of infection with HIV. HIV most often spreads through unprotected sex with an infected person. It may also spread by sharing drug needles or through contact with the blood of an infected person. Since the beginning of the epidemic, almost 78 million people have been infected with the HIV virus and about 39 million people have died of HIV. Globally, 35.0 million people were living with HIV at the end of 2013. Sub-Saharan Africa remains most severely affected, with nearly 1 in every 20 adults living with HIV and accounting for nearly 71% of the people living with HIV worldwide. An estimated 0.8% of adults aged 15–49 years worldwide are
The data and conclusions included in this report are confidential and proprietary information of Marketing Authorisation Applicant pg. 63 Risk Management Plan Emtricitabine/Tenofovir disoproxil RMP Version 3.0 living with HIV. There is no cure for HIV, but early detection and effective treatment with medicines that stop the virus multiplying and allowing patients to stay healthy and live longer.
Pre-exposure prophylaxis (PrEP): Progress in treatment and prevention of HIV has been remarkable. Highly effective antiretroviral (combination of multiple drugs used to treat HIV) therapy for HIV became available in 1996 and has dramatically changed disease survival as well as quality of life for those receiving treatment. Indeed, the number of people living with HIV/AIDS continues to increase, in part, due to the expanding availability of antiretroviral therapy and extension of lifespan. Pre-exposure prophylaxis or PrEP is the use of an antiretroviral medication to prevent the acquisition of HIV infection by uninfected persons. PrEP may either be taken by mouth, using an antiretroviral drug available for treatment of HIV infection (tenofovir plus emtricitabine), or topically as a vaginal gel containing tenofovir. The efficacy of oral PrEP has been shown in four clinical trials and is high when the drug is used as directed. The efficacy of gel has been shown in one trial and is moderate. As of September 2015, WHO recommends that people at considerable risk of HIV infection should be offered PrEP as an additional prevention choice, as part of comprehensive prevention.
VI.2.2 Summary of treatment benefits
In one study, total 254 HIV-1 infected patients received emtricitabine, tenofovir disoproxil fumarate and efavirenz once daily or a fixed combination of lamivudine and zidovudine administered twice daily and efavirenz once daily for 48 weeks and 144 weeks. The 48- week’s data showed that the combination of emtricitabine, Tenofovir disoproxil fumarate and efavirenz have proved more antiviral effect as compared with the fixed combination of lamivudine and zidovudine with efavirenz.
In another study, 190 HIV-1 infected adult patients were treated once daily with emtricitabine and tenofovir disoproxil fumarate in combination with lopinavir/ritonavir given once or twice daily. At 48 weeks, 70% and 64% of patients shows improvement due to therapy with once and twice daily treatment of lopinavir/ritonavir.
The data and conclusions included in this report are confidential and proprietary information of Marketing Authorisation Applicant pg. 64 Risk Management Plan Emtricitabine/Tenofovir disoproxil RMP Version 3.0 Moreover clinical experience in patients infected with HIV and Hepatitis-B suggests that treatment with emtricitabine or tenofovir disoproxil fumarate in combination therapy to control HIV infection also results in improvement of Hepatitis-B.
VI.2.3 Unknowns relating to treatment benefits
The effectiveness of Emtricitabine/Tenofovir disoproxil has not been established in the children less than 18 years and in elderly patient.
VI.2.4 Summary of safety concerns
Important identified risks
Risk What is known Preventability
Post-treatment hepatic Patients with liver disease including Talk to your doctor if you flares in HBV infected chronic hepatitis B or C, who are have a history of liver disease, patients treated with antiretrovirals including hepatitis.
[Exacerbations of liver Emtricitabine/Tenofovir disoproxil, Know your hepatitis B virus related events in HBV have a higher risk of severe and (HBV) infection status before (Hepatitis B Virus- potentially fatal liver starting that cause potentially complications. Emtricitabine/Tenofovir life-threatening liver disoproxil. If you have HBV, infection) infected there is a serious risk of liver patients] problems when you stop taking Emtricitabine/Tenofovir disoproxil, whether or not you also have HIV.
Do not stop taking
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Risk What is known Preventability
Emtricitabine/Tenofovir disoproxil without contacting your doctor.
If you have HIV infection and hepatitis B, it is especially important not to stop your Emtricitabine/Tenofovir disoproxil treatment without talking to your doctor first. Some patients have had blood tests or symptoms indicating that their hepatitis has got worse after stopping Emtricitabine/Tenofovir disoproxil. You may require blood tests for several months after stopping treatment. In some patients with advanced liver disease or cirrhosis, stopping treatment is not recommended as this may lead to worsening of your hepatitis, which may be life- threatening. Tell your doctor immediately about new or unusual symptoms after you stop
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Risk What is known Preventability
treatment, particularly symptoms you associate with hepatitis B infection
HIV-1 acquisition, The effectiveness of HIV-1 uninfected individuals including infection Emtricitabine/Tenofovir disoproxil should be counselled to resulting from non- in reducing the risk of acquiring strictly adhere to the adherence HIV-1 is strongly correlated with recommended (Development of HIV- adherence as demonstrated by Emtricitabine/Tenofovir 1, including infection measurable drug levels in blood. disoproxil dosing schedule. by not following the prescribed recommendations for treatment)
Development of There have been reports of a high Always take the dose resistance in patients rate of emergence of resistance at recommended by your doctor. with unrecognized or an early stage in HIV-1 infected This is to make sure that your acute (sudden onset) patients when tenofovir disoproxil medicine is fully effective, HIV-1 infection fumarate was combined with and to reduce the risk of lamivudine and abacavir as well as developing resistance to the with lamivudine and didanosine as treatment. Do not change the a once daily regimen. There is close dose unless your doctor tells structural similarity between you to. lamivudine and emtricitabine and Individuals should be re- similarities in the movement of confirmed to be HIV-negative drugs within the body and body’s at frequent intervals (e.g. at reaction to it of these two agents. least every 3 months) using a
Emtricitabine/Tenofovir disoproxil combined antigen/antibody test while taking
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Risk What is known Preventability
should only be used to reduce the Emtricitabine/Tenofovir risk of acquiring HIV-1 in disoproxil for pre-exposure individuals confirmed to be HIV prophylaxis (preventive negative treatment to maintain health and prevent the spread of disease)
Renal Toxicity Inflammation of the kidney, passing While taking (Adverse effects on a lot of urine and feeling thirsty, Emtricitabine/Tenofovir kidney) kidney failure, damage to kidney disoproxil to treat HIV or to tubule cells are rare side effect reduce the risk of getting which may affect up to 1 in 1,000 HIV:
people. Emtricitabine/Tenofovir Damage to kidney tubule cells may disoproxil may affect your be associated with breakdown of kidneys. Before and during muscle, softening of the bones treatment, your doctor may (with bone pain and sometimes order blood tests to measure resulting in fractures), muscle pain, kidney function. Tell your muscle weakness and decreases in doctor if you have had kidney potassium or phosphate in the blood disease, or if tests have shown are rare side effect which may kidney problems with your affect up to 1 in every 1,000 kidneys. patients. Emtricitabine/Tenofovir
Breakdown of muscle, muscle pain disoproxil may affect your or weakness which may occur due kidneys. to damage to the kidney tubule cells Before starting treatment, your doctor may order blood are uncommon side effects which may affect up to 1 in 100 people. tests to assess kidney
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Risk What is known Preventability
function. Your doctor may Back pain caused by kidney also order blood tests during problems is a rare side effect which treatment to monitor your may affect up to 1 in 1,000 patients. kidneys and. If you have kidney problems, your doctor Bone problems (sometimes may advise you to stop taking resulting in fractures) may also or, if you already have HIV, occur due to damage to kidney may advise you to take the tubule cells. tablets Emtricitabine/Tenofovir disoproxil less often frequently.
Emtricitabine/Tenofovir disoproxil is not recommended if you have severe kidney disease or are on dialysis.
Taking Emtricitabine/Tenofovir disoproxil with other medicines that can damage your kidneys: It is especially important to tell your doctor if you are taking any of these medicines , including • aminoglycosides (for bacterial infection)
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Risk What is known Preventability
• amphotericin B (for fungal infection) • foscarnet (for viral infection) • ganciclovir (for viral infection) • pentamidine (for infections) • vancomycin (for bacterial infection) • interleukin-2 (to treat cancer) • cidofovir (for viral infection) • non-steroidal anti- inflammatory drugs (NSAIDs, to relieve bone or muscle pains)
If you are taking another antiviral medicine called a protease inhibitor to treat HIV, your doctor may order blood tests to closely monitor your kidney function
Bone events due to Bone problems (sometimes If you think that you may proximal renal resulting in fractures) may also have any of these serious side
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Risk What is known Preventability
tubulopathy/loss of occur due to damage to kidney effects, talk to your doctor.
bone mineral density tubule cells. It is especially important to (Side effects to bone Softening of the bones (with bone tell your doctor if you are due to disorders of pain and sometimes resulting in taking other medicines which essential structures in fractures), damage to kidney tubule may damage your kidneys. kidney gland and it cells may be associated with These include: performs the vital breakdown of muscle, softening of function of the bones (with bone pain and • aminoglycosides (for reabsorbing sodium sometimes resulting in fractures), bacterial infection) salts from the blood muscle pain, muscle weakness and • amphotericin B (for fungal stream/loss of minerals decreases in potassium or infection) like calcium other phosphate in the blood are rare side • foscarnet (for viral types of minerals in effects which may affect up to 1 in infection) bone) 1,000 patients. • ganciclovir (for viral infection) • pentamidine (for infections) • vancomycin (for bacterial infection) • interleukin-2 (to treat cancer) • cidofovir (for viral infection)
• non-steroidal anti- inflammatory drugs (NSAIDs, to relieve bone or muscle pains)
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Risk What is known Preventability
Interaction with Taking Emtricitabine/Tenofovir Your doctor will carefully didanosine (used for disoproxil with other antiviral consider whether to treat you treatment of viral medicines that contain didanosine with combinations of infection) can raise the levels of didanosine in tenofovir and didanosine.
your blood and may reduce CD4 cell counts. Rarely, inflammation of the pancreas and lactic acidosis (excess lactic acid in the blood), which sometimes causes death, have been reported when medicines containing Tenofovir disoproxil and didanosine were taken together.
Pancreatitis Inflammation of the pancreas has If you think that you may (Inflammation of been reported rarely with use of have any of these serious side pancreas- organ Emtricitabine/Tenofovir disoproxil. effects, talk to your doctor.
located in abdomen) It has been reported that, when Tell your doctor or pharmacist medicines containing tenofovir if you are taking, have disoproxil and didanosine were recently taken or might take taken together, it causes any other medicines. inflammation of the pancreas which sometimes causes death.
Pain in the abdomen (tummy) caused by inflammation of the pancreas is an uncommon side effect which may affect up to 1 in 100 patients.
Missing information
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Risk What is known
Safety in children (including long-term Due to insufficient safety data, safety) Emtricitabine/Tenofovir disoproxil is not for use in children and adolescents under 18 years of age.
Safety in elderly patients Emtricitabine/Tenofovir disoproxil has not been studied in patients over 65 years of age.
Safety in pregnancy If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor or pharmacist for advice before taking this medicine.
Although there are limited clinical data on the use of Emtricitabine/Tenofovir disoproxil in pregnant women, it is not usually used unless absolutely necessary.
If you are a woman who could get pregnant during treatment with Emtricitabine/Tenofovir disoproxil, you must use an effective method of contraception to avoid becoming pregnant.
If you become pregnant, or plan to become pregnant, ask your doctor about the potential benefits and risks of therapy with Emtricitabine/Tenofovir disoproxil to you and your child.
If you have taken Emtricitabine/Tenofovir
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Risk What is known
disoproxil during your pregnancy, your doctor may request regular blood tests and other diagnostic tests to monitor the development of your child. In children whose mothers took NRTIs (medicines which are used to treat HIV infection) during pregnancy, the benefit from the protection against HIV outweighed the risk of side effects.
Safety in lactation If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor or pharmacist for advice before taking this medicine.
Do not breast-feed during treatment with Emtricitabine/Tenofovir disoproxil. This is because the active substances in this medicine pass into human breast milk.
If you are a woman with HIV it is recommended that you do not breast-feed, to avoid passing the virus to the baby in breast milk
Safety in patients with renal impairment Emtricitabine/Tenofovir disoproxil may affect (kidney problems) your kidneys. Before starting treatment, your doctor may order blood tests to measure kidney function.
If you have kidney problems, your doctor may advise you to stop taking Emtricitabine/Tenofovir disoproxil or, if you already have HIV, to take less frequently. Emtricitabine/Tenofovir
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Risk What is known
disoproxil is not recommended if you have severe kidney disease or are on dialysis.
VI.2.5 Summary of risk minimisation measures by safety concern
The medicine have a Summary of Product Characteristics (SmPC) which provides physicians, pharmacists and other health care 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 (PL). The measures in these documents are known as routine risk minimisation measures.
This medicine has special conditions and restrictions for its safe and effective use (additional risk minimisation measures). As suggested by the competent authority,
• The additional risk minimisation measures related to the tenofovir-containing products and important identified risk of “renal toxicity”, the need for additional risk minimisation measures (HIV renal educational brochure - educational material for all physicians who are expected to prescribe/use tenofovir/emtricitabine) and
• Physician educational pack containing the Summary of Product Characteristics and an appropriate educational brochure for indication of “Pre-exposure prophylaxis (PrEP)” for the important identified risks of “HIV-1 Acquisition, including infection resulting from non-adherence’ and “Development of resistance in patients with unrecognized or acute HIV-1 infection”. Renal Toxicity
Physicians
Objective and rationale:
Physicians to understand the risk of occurrence of renal toxicity and the appropriate management of this risk to minimise its occurrence and its severity.
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Physicians
Proposed action:
The HIV renal educational brochure to be provided to prescribing physicians, should contain the following key messages:
• That there is an increased risk of renal disease in HIV infected patients associated with tenofovir disoproxil fumarate-containing products such as Emtricitabine/Tenofovir disoproxil. • That Emtricitabine/Tenofovir disoproxil should only be used in patients with impaired renal function if the potential benefits are considered to outweigh the potential risks. • That use of Emtricitabine/Tenofovir disoproxil should be avoided with concomitant or recent use of nephrotoxic medicinal products. If Emtricitabine Tenofovir disoproxil is used with nephrotoxic medicinal products, renal function should be closely monitored according to the recommended schedule • That patients should have their baseline renal function assessed prior to initiating Emtricitabine Tenofovir disoproxil therapy The importance of regular monitoring of renal function during Emtricitabine/Tenofovir disoproxil therapy. • Recommended schedule for monitoring renal function considering the presence or absence of additional risk factors for renal impairment. • Instructions on the use of the creatinine clearance slide ruler.
Indication of Pre-exposure prophylaxis (PrEP)
Physicians
Objective and rationale:
Physicians to understand the risks of occurrence of “post-treatment hepatic flares in HBV infected patients” and risk of “HIV-1 acquisition, including infection resulting from non- adherence” and the appropriate management of this risk to minimise its occurrence and its
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Physicians
severity.
Proposed action:
Physicians who are expected to prescribe/use Emtricitabine/Tenofovir disoproxil in adult patients are provided with a physician educational pack containing the Summary of Product Characteristics and an appropriate educational brochure should contain:
PrEP educational brochure for prescribers:
• Reminder of the key safety information regarding the use of Emtricitabine Tenofovir disoproxil for PrEP • Reminder of factors to help identify individuals at high risk of acquiring HIV-1 • Reminder on the risk of development of HIV-1 drug resistance in undiagnosed HIV-1– Infected individuals • Provides safety information on adherence, HIV testing, renal, bone and HBV status.
PrEP Checklist for prescribers:
• Reminders for evaluations/counselling at the initial visit and follow-up.
PrEP educational brochure for the individual at risk (to be provided by healthcare provider [HCP]):
• Reminders on what the individual should know before and while taking Emtricitabine Tenofovir disoproxil to reduce the risk of getting HIV infection • Reminder on the importance of strict adherence to the recommended dosing regimen• Provides information on how to take Emtricitabine Tenofovir disoproxil • Provides information on the possible side effects • Provides information on how to store Emtricitabine Tenofovir disoproxil
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Physicians
PrEP reminder card for the individual at risk (to be provided by HCP):
• Reminders to adhere to the dosing schedule • Reminder to attend scheduled clinic visits.
VI.2.6 Planned post authorisation development plan
No studies planned.
VI.2.7 Summary of changes to the risk management plan over time
Version Date Safety Concern Comment
3.0 31 January No change in safety concern. RMP has been updated as 2017 regulatory has requested MAH to remove a statement for his enrollment in Antiretroviral Pregnancy Registry (APR) from RMP in Day 120 assessment report.
2.0 06 October Importa • Post- The safety concern and 2016 nt treatment relevant sections have been identifie hepatic changed based on d risks flares in recommendations/comments (s) HBV received by competent infected authority.
patients Additional Risk
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Version Date Safety Concern Comment
• HIV-1 minimisation measures have acquisition, been proposed for safety including concerns Important infection identified risks: “HIV-1 resulting acquisition, including from non- infection resulting from adherence non-adherence”, (PrEP “Development of resistance indication) in patients with unrecognized or acute HIV- • Developme 1 infection” and “Renal nt of toxicity”. resistance in patients Antiretroviral Pregnancy with Registry (APR) has been unrecogniz proposed as an additional ed or acute pharmacovigilance activity HIV-1 for the safety concern infection “Safety in pregnancy” (PrEP indication)
• Renal toxicity
• Bone events due to proximal renal tubulopath
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Version Date Safety Concern Comment
y/loss of BMD
• Interaction with didanosine
• Pancreatiti s
Importa • None nt potential risks
Missing • Safety in informati children on (Including long-term safety)
• Safety in elderly patients
• Safety in pregnancy
• Safety in lactation
• Safety in patients
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Version Date Safety Concern Comment
with renal impairment
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