Risk Management Plan Emtricitabine/Tenofovir (As Phosphate) V1.1

Risk Management Plan Emtricitabine/Tenofovir (as phosphate) V1.1

VI.2 Elements for a Public Summary

VI.2.1 Overview of disease epidemiology Human immunodeficiency virus (HIV) is a virus that attacks the body’s natural defense system and causes Acquired Immunodeficiency Syndrome (AIDS). AIDS refers to the range of infections/illnesses which result from a weakened immune system. HIV is transmitted through sexual contact (commonest), infected blood transfusions, needle sharing and to an unborn child from a HIV-positive mother. In 2013, 136,235 new HIV infections were diagnosed in 51 of the 53 countries of the WHO European Region. In 2013, 29,157 HIV diagnoses were reported by 30 EU/EEA countries, with a rate of 5.7/100,000 population (men 8.9; women 2.6 per 100,000 population). In 2013, countries with highest rates of HIV diagnoses were in Estonia (24.6), Latvia (16.8), Portugal (10.4), and Belgium (10.0), and lowest rates were in Slovakia (1.5) and Croatia (2.0). There are nearly 110,000 people living with HIV and in 2013, less than 1% of people with HIV died in the UK.

VI.2.2 Summary of treatment benefits Emtricitabine/Tenofovir 200 mg/245 mg is a medicine that contains two active substances, Emtricitabine (200 mg) and Tenofovir (245 mg).

Emtricitabine/Tenofovir is used in combination with at least one other antiviral medicine (medicines used to treat HIV) to treat patients over 18 years old who are infected with HIV, the virus that causes AIDS. It does not completely cure HIV infection; it reduces the amount of virus in your body, and keeps it at a low level. It can also be used to help preventing sexually transmitted HIV-1 infections in adults who are at high risk of being infected (‘pre-exposure prophylaxis’). It should be used in combination with safer sex practices, such as use of condoms.

A study examined the effects of Emtricitabine and Tenofovir disoproxil in adults infected with HIV who had not been treated before. This study compared the combination of Emtricitabine and Tenofovir with the combination of Lamivudine and Zidovudine (other medicines used in HIV), both taken with Efavirenz (other medicine used in HIV) in 255 patients. At 48 weeks, Emtricitabine and tenofovir disoproxil with efavirenz provided superior effectiveness as compared with combination of Lamivudine and Zidovudine (Combivir) with efavirenz.

Studies have evaluated pre-exposure prophylaxis with Emtricitabine and Tenofovir in addition to other preventive measures and compared it with placebo (a dummy treatment), in adults at high risk of sexually transmitted HIV-1 infection. The main measure of effectiveness was the number of adults at high risk for acquiring HIV-1 who tested positive for HIV-1 infection. Emtricitabine and Tenofovir was more effective than placebo for preventing HIV-1 infection.

VI.2.3 Unknowns relating to treatment benefits There is limited information on the use of Emtricitabine/Tenofovir in the following groups:  Special care is advised in patients over 65 years of age due to age associated changes such as the decrease in renal (kidney) function.  Emtricitabine/Tenofovir is not recommended for the treatment of children less than 18 years of age as insufficient safety data are available for children below 18 years of age.  Data on pregnant women indicates no malformations or foetal/neonatal toxicity (no harmful effects on the child) associated with Emtricitabine and Tenofovir. Therefore the use of Emtricitabine and Tenofovir disoproxil may be considered during pregnancy, if necessary.  Emtricitabine and Tenofovir have been shown to be excreted in human milk. There is insufficient information on the effects of Emtricitabine and Tenofovir in newborn/infants. Therefore Emtricitabine and Tenofovir should not be used during breast-feeding.  There are limited data on the safety and efficacy of Emtricitabine and Tenofovir in patients with moderate and severe renal impairment (kidney dysfunction) and long-term safety data has not been evaluated for mild renal impairment.

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Risk Management Plan Emtricitabine/Tenofovir (as phosphate) V1.1

VI.2.4 Summary of safety concerns

Table 9: Important Identified Risk(s) Risk(s) What is known Preventability [liver problems If you have HIV infection and hepatitis B, it 1. Doctors can closely monitor on stopping is especially important not to stop treatment patients co-infected with HIV treatment in with Emtricitabine/Tenofovir without talking and HBV clinically and patients who to your doctor first. Some patients have had laboratory follow-up for at least have HIV and blood tests or symptoms indicating that their several months after stopping hepatitis B (a hepatitis (liver disorder) has got worse after treatment with type of liver stopping Emtricitabine/Tenofovir.The patient Emtricitabine/Tenofovir. disorder)][(Post- may require blood tests for several months treatment after stopping treatment. In some patients hepatic flares in with advanced liver disease or cirrhosis (a 2. Patients are advised to discuss HIV-1/HBV co- serious liver disorder), stopping treatment is with their doctors prior to infected not recommended as this may lead to stopping Patients worsening of hepatitis. Emtricitabine/Tenofovir.Inform the treating doctor immediately about new or unusual symptoms after stopping Emtricitabine/Tenofovir particularly, the symptoms with hepatitis B infection. Renal (kidney) The tenofovir disoproxil component has been 1. Doctors are advised to regularly toxicity (harmful associated with kidney problems. Before monitor renal functions in effect) starting treatment, your doctor may order patients who are susceptible to blood tests to assess kidney function. Your kidney impairment. doctor may also order blood tests during treatment to monitor your kidneys and may 2. Patients with renal impairment advise you to take the tablets less often. may require close monitoring of Emtricirtabine/Tenofovir is not recommended kidney function. if you have severe kidney disease or are receiving haemodialysis.

Emtricirtabine/Tenofovir is not usually taken with other medicines that can damage your kidneys. If this is unavoidable, your doctor will monitor your kidney function once a week.

The following side effects are rare (these can affect up to 1 in every 1,000 patients): inflammation of the kidney, passing a lot of urine and feeling thirsty, kidney failure, damage to kidney tubule cells. Your doctor may do blood tests to see if your kidneys are working properly. Bone events due Damage to kidney tubule cells may be 1. Doctors should be aware of the to proximal renal associated with breakdown of muscle, potential for bone problems and tubulopathy softening of the bones (with bone pain and monitor kidney function at the (type of kidney sometimes resulting in fractures), muscle start of treatment and during disease)/loss of pain, muscle weakness and decreases in treatment. bone mineral potassium or phosphate in the blood. Confidential Page 33 of 40

Risk Management Plan Emtricitabine/Tenofovir (as phosphate) V1.1

density (decrease in minerals in bones) Drug interaction Taking Emtricitabine/Tenofovir with other 1. Doctors are advised to avoid with an anti-HIV antiviral medicines that contain Didanosine prescribing Emtricitabine/ medicine called can raise the levels of Didanosine in your Tenofovir together with Didanosine blood and may reduce CD4 cell counts (a type Didanosine. of cell). Rarely, inflammation of the pancreas and lactic acidosis (excess lactic acid in the 2. Patients are advised to blood), which sometimes causes death, have immediately inform their been reported when medicines containing doctors about all the Tenofovir disoproxil and Didanosine were medications they are taking taken together. Your doctor will carefully prior to starting treatment with consider whether to treat you with Emtricitabine/Tenofovir. combinations of Tenofovir and Didanosine. Pancreatitis The tenofovir disoproxil component has been 1. Doctors should be aware of the (inflammation of associated with a side effect of pancreatitis potential for pancreatitis and pancreas) (inflammation of the pancreas). The risk of consider stopping treatment if pancreatitis is low: in clinical trials, the necessary. frequency of pancreatitis was 0.2% (1 in 500 patients). Development of Emtricitabine/Tenofovir disoproxil 200 1. Doctors should be aware of the resistance in mg/245 mg Film-coated Tablets should only potential for resistance with patients with be used to reduce the risk of acquiring HIV-1 Pre-exposure prophylaxis unrecognized or in individuals confirmed to be HIV negative (PrEP) in undetected HIV-1 acute HIV-1 infection. infection (prior to the exposure to prevent an infection) HIV-1 Non-adherence to dosage schedule and 1. Doctors should instruct patients acquisition, instruction provided with regarding importance of including Emtricitabine/Tenofovir disoproxil 200 adherence to schedule and infection mg/245 mg Film-coated Tablets may result in instructions and monitor resulting from lack of effect for PrEP indication patients on PrEP. non-adherence ( 2. Patients should be aware of prior to the possibility of acquisition or exposure to infection with HIV-I while of prevent an PrEP infection)

Table 10: Important Potential Risk(s)

Risk(s) What is known None Not applicable

Table 11: Missing Information Risk(s) What is known Safety in children Emtricitabine/Tenofovir is not recommended in children under the age of 18 years (including long- as the safety and efficacy of Emtricitabine/Tenofovir have not been established in term safety) this population. Confidential Page 34 of 40

Risk Management Plan Emtricitabine/Tenofovir (as phosphate) V1.1

Risk(s) What is known Safety in elderly Emtricitabine/Tenofovir has not been studied in patients over the age of 65. patients Elderly patients are more likely to have decreased renal (kidney) function; therefore caution should be exercised when treating elderly patients with Emtricitabine/Tenofovir. Safety in pregnancy Data on pregnant women indicates no malformations or foetal/neonatal toxicity and lactation associated with Emtricitabine and Tenofovir disoproxil. Therefore the use of Emtricitabine/Tenofovir may be considered during pregnancy, if necessary.

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. Therefore Emtricitabine/Tenofovir should not be used during breast-feeding.

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. Safety in patients The Tenofovir disoproxil component is removed from the blood by the kidney with kidney and the amount of tenofovir increases in patients with kidney problems. In problems patients with kidney problems, Emtricitabine/Tenofovir 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 patients with moderate kidney problems. Emtricitabine/Tenofovir 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 All medicines 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). Full details on these conditions and the key elements of any educational material can be found in Annex II of the product information which is published in Emtricitabine/Tenofovir 200 mg/245 mg Film-coated Tablets’ EPAR page; how they are implemented in each country; however, will depend upon agreement between the manufacturer and the national authorities.

These additional risk minimisation measures are for the following risk:

Renal toxicity Risk minimisation measure(s)

 Educational material (renal educational brochure including creatinine clearance slide ruler for prescribers )  The educational material will be discussed and agreed with the national competent authority prior to actual launch of the product in the market. Objective and rationale: The additional risk minimization activities have been planned so as to: Confidential Page 35 of 40

Risk Management Plan Emtricitabine/Tenofovir (as phosphate) V1.1

 Renal toxicity is an important identified risk of Tenofovir. The additional risk minimization activities have been planned so that healthcare professional (HCPs) are provided with educational material that act as a quick reference tools to reduce the incidence of number of cases and/or frequency of renal toxicity.  The Renal educational brochure provides important points to consider, data on clinical and post- marketing studies, table on monitoring of renal function and use in renal impairment, creatinine clearance slide ruler, and relevant information from the SmPC. Summary description of main additional risk minimisation measures:

Educational material (renal educational brochure including creatinine clearance slide ruler for prescribers. The educational material will be discussed and agreed with the national competent authority prior to actual launch of the product in the market.

Development of resistance in patients with unrecognized or acute HIV-1 infection (PrEP indication) Risk minimisation measures:  Educational material (PrEP educational brochure for prescribers and for individuals at risk along with Checklist for prescribers and Patient reminder card).

 The educational material will be discussed and agreed with the national competent authority prior to actual launch of the product in the market. Objective and rationale: The additional risk minimization activities have been planned:

 Development of resistance in patients with unrecognized or acute HIV-1 infection when used for PrEP indication, is an important identified risk of Emtricitabine/ Tenofovir. The additional risk minimization activities have been planned so that HCPs are provided with educational material that act as a quick reference tools to prevent development of resistance in patients with unrecognized or acute HIV-1 infection (PrEP indication).

PrEP educational brochure for prescribers:  Reminder of the key safety information regarding the use of Tenofovir Disoproxil/ Emtricitabine 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 Tenofovir Disoproxil/ Emtricitabine 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 Tenofovir Disoproxil/ Emtricitabine  Provides information on the possible side effects

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Risk Management Plan Emtricitabine/Tenofovir (as phosphate) V1.1

 Provides information on how to store Tenofovir Disoproxil/ Emtricitabine.

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.

The educational material will be discussed and agreed with the national competent authority prior to actual launch of the product in the market.

HIV-1 acquisition, including infection resulting from non-adherence (PrEP indication) Risk minimisation measures:  Educational material (PrEP educational brochure for prescribers and for individuals at risk along with Checklist for prescribers and Patient reminder card).

 The educational material will be discussed and agreed with the national competent authority prior to actual launch of the product in the market. Objective and rationale:

The additional risk minimization activities have been planned:

 HIV-1 acquisition, including infection resulting from non-adherence, when used for PrEP indication, is an important identified risk of Emtricitabine/ Tenofovir. The additional risk minimization activities have been planned so that HCPs are provided with educational material that act as a quick reference tools to prevent development of resistance in patients with unrecognized or acute HIV-1 infection (PrEP indication).

 The educational brochures, checklist for prescriber and patient reminder card provides important points to consider before starting PrEP and points to remember while monitoring individuals on PrEP. Summary description of main additional risk minimisation measures: PrEP educational brochure for prescribers:  Reminder of the key safety information regarding the use of Tenofovir Disoproxil/ Emtricitabine 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.

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Risk Management Plan Emtricitabine/Tenofovir (as phosphate) V1.1

 Provides information on how to store Tenofovir Disoproxil/ Emtricitabine.

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.

The educational material will be discussed and agreed with the national competent authority prior to actual launch of the product in the market.

VI.2.6 Planned post authorisation development plan Not applicable.

VI.2.7 Summary of changes to the Risk Management Plan over time

Version Date Safety Concerns Comments 1.0 10 March 2017 Important Identified Risks: First version of the  Post-treatment hepatic flares in HBV RMP. mono-infected and HIV/HBV co-infected patients  Renal toxicity  Bone events due to proximal renal tubulopathy/loss of BMD  Drug interaction with didanosine  Pancreatitis  Development of resistance in patients with unrecognized or acute HIV-1 infection (PrEP indication)  HIV-1 acquisition, including infection resulting from non-adherence (PrEP indication)

Important Potential Risks None

Missing information:  Safety in children (including long-term safety)  Safety in elderly patients  Safety in pregnancy and lactation  Safety in patients with renal impairment 1.1 25 April 2017 The following safety concern was updated: Based on assessor’s comments Part V has Important Identified Risk been updated so that  Development of resistance in patients with the targeted follow-up unrecognised or acute HIV-1 infection forms are considered as (PrEP indication). (previously “Risk of pharmacovigilance resistance with Pre-exposure prophylaxis measures, and not risk (PrEP) in undetected HIV-1 infection”) minimisation measures.

The following safety concern was added: Confidential Page 38 of 40

Risk Management Plan Emtricitabine/Tenofovir (as phosphate) V1.1

Version Date Safety Concerns Comments Revelant sections of the Important Identified Risk RMP are updated. HIV-1 acquisition, including infection resulting from non-adherence (PrEP indication)

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