VI.2 Elements for a Public Summary VI.2.1 Overview of Disease Epidemiology

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1 VI.2 Elements for a Public Summary VI.2.1 Overview of Disease Epidemiology HIV stands for human immunodeficiency virus. If left untreated, HIV can lead to the disease AIDS (acquired immunodeficiency syndrome). Unlike some other viruses, the human body can t get rid of HIV completely, so once you have HIV, you have it for life. HIV attacks the body s immune system, specifically the CD4 cells (T cells), which help the immune system fight off infections. If left untreated, HIV reduces the number of CD4 cells (T cells) in the body, making the person more likely to get infections or infection-related cancers. Over time HIV can destroy so many of these cells that the body can t fight off infections and disease. These opportunistic infections or cancers take advantage of a very weak immune system and signal that the person has AIDS, the last state of HIV infection. In 2012, new AIDS cases were over three times higher in the east than in the west and the centre of Europe. While reported AIDS cases declined by 54% in the west, the number of people newly diagnosed with AIDS increased by 113% in the east between 2006 and Between 2006 and 2012, reported deaths among people with AIDS decreased by 14% across the WHO European Region as a whole, and increased by 58% in the east only. According to the Joint United Nations Programme on HIV/AIDS (UNAIDS) and WHO/Europe, the numbers of estimated deaths were as high as 91,000 in Eastern Europe and central Asia, and 7,600 in Western and Central Europe: an almost 12-fold difference 3. In 2012, 29,381 HIV diagnoses were reported by 30 EU/EEA countries, with a rate of 5.8 per 100,000 population. The five countries with the highest rates of HIV diagnoses in 2012 were Estonia (23.5), Latvia (16.6), Belgium (11.1), the United Kingdom (10.3), and Luxembourg (10.3). The lowest rates were reported by Slovakia (0.9) and Croatia (1.7). Since the start of reporting on the HIV epidemic, 455,757 HIV diagnoses have been reported in the EU/EEA; 324,181 were in men and 128,325 in women, 3,251 not having gender information available. In 2012, the male-to-female ratio was 3.2. Young people 15 to 24 years of age accounted for 10.6% of all HIV diagnoses reported, but this varied widely from 4.4% in Slovenia to 32.5% in Romania. Similar to recent years, the highest proportion of HIV diagnoses was reported in men who have sex with men (40.4%), followed by heterosexual transmission (33.8%), including heterosexually-acquired cases originating from sub-saharan African countries. For 18.7% of the cases the transmission mode was unknown. The rate of HIV diagnoses per 100,000 population appears to have remained fairly stable over time, with a rate of 6.4 per 100,000 in 2006 (28,318 cases) compared to 6.2 per 100,000 (30,900 cases) in 2012 when adjusted for reporting delay. In 2012, 131,202 new HIV infections were diagnosed in 52 of the 53 countries of the WHO European Region. Of those infections, 55,494 were officially reported to ECDC/WHO Regional Office for Europe by 51 countries, while 75,708 infections were reported through the database of the Federal Statistics Agency of the Russian Federation. Since the beginning of the epidemic and up to December 31 st, 2012, there has been a cumulative total

2 of at least 1,496,201 diagnoses of HIV infection in the WHO European Region. This number includes a cumulative total of 839,337 infections officially reported to ECDC and the WHO Regional Office for Europe, and 719,445 infections reported in Russia as of December 31 st, 2012, minus the 62,581 cases officially reported to ECDC/WHO by Russia in VI.2.2 Summary of Treatment Benefits Emtricitabine and Tenofovir Disoproxil Amneal contains two active substances, emtricitabine and tenofovir disoproxil. Both of these active substances are antiretroviral medicines which are used to treat HIV infection. Emtricitabine is a nucleoside reverse transcriptase inhibitor, and tenofovir is a nucleotide reverse transcriptase inhibitor. However, both are generally known as NRTIs, and they work by interfering with the normal working of an enzyme (reverse transcriptase) that is essential for the virus to reproduce itself. Emtricitabine and Tenofovir Disoproxil Amneal should always be used in combination with other medicines to treat HIV infection. Emtricitabine and Tenofovir Disoproxil Amneal can be administered in place of emtricitabine and tenofovir disoproxil or used separately at the same doses. This medicine is not a cure for HIV infection. While taking Emtricitabine and Tenofovir Disoproxil Amneal patients may still develop infections or other illnesses associated with HIV infection. Patients can still pass on HIV when taking this medicine, although the risk is lowered by effective antiretroviral therapy. VI.2.3 Unknowns Relating to Treatment Benefits The safety and efficacy of Emtricitabine and Tenofovir Disoproxil Amneal in children under the age of 18 years have not yet been established. No data is available on which to make a dose recommendation for patients over 65 years of age. However, no adjustment in the recommended daily dose for adults should be required unless there is evidence of renal insufficiency. A moderate amount of data on pregnant women (between 300 and 1,000 pregnancy outcomes) indicates no malformations or foetal/neonatal toxicity associated with emtricitabine and tenofovir disoproxil fumarate. Animal studies on emtricitabine and tenofovir disoproxil fumarate do not indicate reproductive toxicity. Emtricitabine and tenofovir have been shown to be excreted in human milk. There is insufficient information on the effects of emtricitabine and tenofovir in newborns/infants. Renal safety with Emtricitabine and Tenofovir Disoproxil Amneal has only been studied to a very limited degree in patients with impaired renal function (creatinine clearance < 80 ml/min). Dose interval adjustments are recommended for patients with creatinine clearance 30 to 49 ml/min. Limited clinical study data suggests that the prolonged dose interval is not optimal and could result in increased toxicity and possibly inadequate response. Furthermore, in a small clinical study a subgroup of patients with creatinine clearance between 50 and 60 ml/min who

3 received tenofovir disoproxil in combination with emtricitabine every 24 hours had a 2- to 4- fold higher exposure to tenofovir and worsening of renal function. Therefore, a careful benefitrisk assessment is needed when Emtricitabine and Tenofovir Disoproxil Amneal is used in patients with creatinine clearance < 60 ml/min, and renal function should be closely monitored. In addition, the clinical response to treatment should be closely monitored in patients receiving Emtricitabine and Tenofovir Disoproxil Amneal at a prolonged dosing interval. The use of Emtricitabine and Tenofovir Disoproxil Amneal is not recommended in patients with severe renal impairment (creatinine clearance < 30 ml/min) and in patients who require haemodialysis, since appropriate dose reductions cannot be achieved with the combination table. VI.2.4 Summary of Safety Concerns Important Identified Risks: Risk What is Known Preventability Liver problems in HBV infected patients (Post-treatment hepatic flares in HBV infected patients) Kidney problems (Renal Toxicity) The use of this medicine may be dangerous in patients that have hepatitis. It may cause severe life threatening liver problems. The tenofovir disoproxil component has been associated with kidney problems, including damage to kidney tubule cells, kidney failure, kidney inflammation, passing a lot of urine, and increases in creatinine in blood. The frequency of renal events is very low: in clinical trials involving tenofovir disoproxil, the frequency of increased creatinine was 0.2% (1 in 500 patients), and frequency of kidney failure was 0.06% (3 in 5000 patients). Risk factors for kidney problems include advanced HIV disease (low CD4 count at the start of treatment), low weight, older age, kidney problems before starting therapy, use of other medicines that are damaging to kidneys, high blood pressure, and also being infected with hepatitis C. Yes. The patient should inform their doctor if he or she suffers from hepatitis (inflammation of the liver), and the doctor should check if the patient has hepatitis before starting treatment with this medicine. Yes, by carrying out blood tests for kidney function at the start of treatment and during treatment with Emtricitabine and Tenofovir Disoproxil Amneal 200 mg/245 mg film-coated tablets, by avoiding use of other medicines that may damage the kidneys, and by the doctor considering stopping treatment if necessary.

4 Bone problems (Bone events due to proximal renal tubulopathy/loss of bone mineral density) Damage to kidney tubule cells associated with the tenofovir component can cause bone softening (with bone pain and sometimes resulting in fractures). The frequency of bone softening for bone problems, as described in the Summary of Product Information Leaflet, and by monitoring for renal function at Risk What is Known Preventability Interaction with didanosine Pancreatitis (inflammation of the pancreas) HIV-1 acquisition, including infection resulting from non-adherence is low; in clinical trials, no side effects of bone softening were observed. Thinning of bones (decreases in bone mineral density) have also been observed in patients treated with tenofovir. However, the clinical significance is unknown as no increase in fracture rates has been observed. Taking this medicine with other antiviral medicines that contain didanosine can raise the levels of didanosine in the 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. Your doctor will carefully consider whether to treat you with combinations of tenofovir and didanosine. Rarely, pancreas problems and lactic acidosis, sometimes fatal, have been reported, especially if given with didanosine. Emtricitabine and Tenofovir Disoproxil Amneal 200 mg/245 mg film-coated tablets should only be used for prevention as part of an overall HIV-1 infection strategy the start of treatment and during treatment. Yes. This medicine should not be given to patients taking didanosine. pancreas problems, as described in the Summary of Product Information Leaflet, and by monitoring the function of the pancreas at the start and during treatment, especially in case of didanosine administration. HIV infection, as described in the Summary of Product Information Leaflet and by providing information about safe

5 Risk What is Known Preventability (HIV-1 infection during treatment including infections resulting from not following properly the treatment) Development of resistance in patients with unrecognized or acute HIV-1 infection (ineffectiveness of treatment in patients with other versions of HIV, or those with acute infection) Important Potential Risks: None including the use of other HIV-1 prevention measures (e.g., consistent and correct condom use, knowledge of HIV-1 status, regular testing for other sexually transmitted infections). Emtricitabine and Tenofovir Disoproxil Amneal 200 mg/245 mg film-coated tablets alone does not constitute a complete treatment of HIV-1 and HIV-1 resistance strains that have emerged in individuals with undetected HIV-1 infection who are only taking Emtricitabine and Tenofovir Disoproxil Amneal 200 mg/245 mg film-coated tablets. sex practices such as consistent and correct condom use, knowledge of HIV-1 status, regular testing for other sexually transmitted infections. HIV infection, as described in the Summary of Product Information Leaflet and by providing information the correct dosing regiment and awareness of the HIV status. Missing Information: Risk Limited information on use in children and adolescents (under the age of 18 years) Limited information on use in patients over 65 years of age Limited information on use during pregnancy What is Known Emtricitabine and Tenofovir Disoproxil Amneal is a fixed dose combination tablet and is not considered appropriate for use in children and adolescents under 18 years old who may need weight or age-based modification of the individual active ingredients. This medicine has not been studied in patients over 65 years of age. Elderly patients are more likely to have kidney problems. A moderate amount of data on pregnant women (between 300 and 1,000 pregnancy outcomes) indicates no malformations or foetal/neonatal harm associated with emtricitabine and tenofovir disoproxil fumarate. Animal studies on emtricitabine and tenofovir disoproxil fumarate do not indicate reproductive problems. Limited information during lactation Emtricitabine and Tenofovir Disoproxil have been shown to be excreted in human milk. There is insufficient information on the effects of emtricitabine and tenofovir in newborns/infants. As a general rule, it is recommended that HIV infected women do not breast-feed their infants under any circumstances in order to avoid transmission of HIV to the infant.

6 Limited information on use in patients with kidney problems The tenofovir disoproxil component is removed from the blood by the kidney, and the amount of tenofovir increases in patients with kidney problems. In HIV-1 infected patients with kidney problems, Emtricitabine and Tenofovir Disoproxil Amneal 200 mg/245 mg film-coated tablets should only be used if the potential benefits of treatment are considered by their doctor to outweigh the potential risks. To reduce the risk of side effects, the time between doses should be increased in HIV-1 infected patients with moderate kidney problems. Emtricitabine and Tenofovir Disoproxil Amneal 200 mg/245 mg film-coated tablets is not recommended for use in patients with severe kidney problems, as the dose of the emtricitabine and tenofovir disoproxil components would need to be adjusted in these patients, and this cannot be achieved with the combination tablet. VI.2.5 Summary of Risk Minimisation Measures by Safety Concern The summary of product characteristics (SPC) of Emtricitabine and Tenofovir disoproxil 200 mg/245 mg film coated tablets 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 information leaflet (PIL). All routine risk minimisation measures are described in the SPC and PIL of Emtricitabine and Tenofovir Disoproxil Amneal 200 mg/245 mg film-coated tablets. This medicine has also special conditions and restrictions for its safe and effective use, known as additional risk minimisation measures. The details of proposed additional risk minimisation measures educational material can be found in annex 10 along mock-ups are included in annex 11 of this RMP. These additional risk minimisation measures are for the following risks: Important identified risk- Kidney Problems (renal toxicity) Risk minimisation measure(s) Objective and rationale Healthcare professionals should understand the risk of renal toxicity events and the appropriate management of this risk to minimise its occurrence and its severity Main additional risk minimisation measures Healthcare professionals educational materials (HIV renal educational brochure and HIV paediatric renal educational brochure) to be provided to prescribing physicians and pharmacists including advice on: Monitoring of renal function Monitoring of bone events Use in Renal Impairment Dosing interval adjustments for patients with renal impairment Instructions on the use of the creatinine clearance slide ruler Important identified risks: HIV-1 infection during treatment including infections resulting from not following properly the treatment (HIV-1 acquisition, including infection resulting from nonadherence) And

7 Ineffectiveness of treatment in patients with other versions of HIV, or those with acute infection (Development of resistance in patients with unrecognized or acute HIV-1 infection) Risk minimisation measure(s) Objective and rationale The individuals at risk and healthcare professionals to understand the risk of HIV-1 acquisition, including infection resulting from non-adherence and development of resistance or and the appropriate management of these risks to minimise its occurrence and its severity Main additional risk minimisation measure Health care professionals will be provided with an educational pack containing the SPC and the following: PrEP educational brochure for prescribers entitled Important Safety Information for Prescribers About Emtricitabine/Tenofovir disoproxil 200 mg/245 mg film coated tablets for a Pre-exposure Prophylaxis (PrEP) Indication PrEP Checklist for prescribers The individuals at risk shall be provided with the adequate educational materials by their health care professionals consisting in: PrEP educational brochure for the individual at risk entitled Important Information About Emtricitabine/Tenofovir disoproxil 200 mg/245 mg film coated tablets to Reduce the Risk of getting Human Immunodeficiency Virus (HIV) Infection Risk minimisation measure(s) PrEP reminder card VI.2.6 Planned Post-Authorisation Development Plan No post-authorisation studies are planned for this product. VI.2.7 Summary of Changes to the Risk Management Plan Over Time This is the first RMP for Emtricitabine and Tenofovir Disoproxil Amneal 200 mg/245 mg filmcoated tablets.