EMTRICITABINE/ TENOFOVIR DISOPROXIL

Emtricitabine/ Tenofovir disoproxil should be initiated by a physician experienced in the management of HIV infection. Posology Treatment of HIV in adults and adolescents aged 12 years and older, weighing at least 35 kg: One tablet, once daily.

Prevention of HIV in adults and adolescents aged 12 years and older, weighing at least 35 kg: One tablet, once daily. Separate preparations of emtricitabine and tenofovir disoproxil fumarate are available for treatment of HIV-1 infection if it becomes necessary to discontinue or modify the dose of one of the components of Emtricitabine/ Tenofovir disoproxil.

Please refer to the Summary of Product Characteristics for these medicinal products If a dose of Emtricitabine/ Tenofovir disoproxil is missed within 12 hours of the time it is usually taken, Emtricitabine/ Tenofovir disoproxil should be taken as soon as possible and normal dosing schedule should be resumed.

If a dose of Emtricitabine/ Tenofovir disoproxil is missed by more than 12 hours and it is almost time for their next dose, the missed dose should not be taken and the usual dosing schedule should be resumed. If vomiting occurs within 1 hour of taking Emtricitabine/ Tenofovir disoproxil, another tablet should be taken.

If vomiting occurs more than 1 hour after taking Emtricitabine/ Tenofovir disoproxil a second dose should not be taken. 2). 2).

Adults with renal impairment:

Emtricitabine and tenofovir disoproxil should only be used in individuals with creatinine clearance (CrCl) < 80mL/min if the potential benefits are considered to outweigh the potential risks. See Table 1. 4). Limited data from clinical studies support once daily dosing of Emtricitabine/ Tenofovir disoproxil in HIV-1 uninfected individuals with CrCl 60- 80 mL/min.

2). Moderate renal impairment (CrCl 30-49 mL/min) Administration of Emtricitabine/ Tenofovir disoproxil every 48 hours is recommended based on modelling of single-dose pharmacokinetic data for emtricitabine and tenofovir disoproxil fumarate in non- HIV infected subjects with varying degrees of renal impairment (see section Emtricitabine/ Tenofovir disoproxil is not recommended for use in this population.

4). Severe renal impairment (CrCl <30mL/min) and haemodialysis patients Emtricitabine/ Tenofovir disoproxil is not recommended because appropriate dose reductions cannot be achieved with the combination tablet. Emtricitabine/ Tenofovir disoproxil is not recommended for use in this population.

4). 2). 2). Method of administration Oral administration. It is preferable that Emtricitabine/ Tenofovir disoproxil is taken with food. Emtricitabine/ Tenofovir disoproxil can be disintegrated in approximately 100 ml of water, orange juice or grape juice and taken immediately.

1). The safety profile of emtricitabine and tenofovir disoproxil fumarate in this study was consistent with the previous experience with these agents when each was administered with other antiretroviral agents.

Pre-exposure prophylaxis:

No new adverse reactions to Emtricitabine/ Tenofovir disoproxil were identified from two randomised placebo-controlled studies (iPrEx, Partners PrEP) in which 2,830 HIV-1 uninfected adults received Emtricitabine/ Tenofovir disoproxil once daily for pre-exposure prophylaxis.

Patients were followed for a median of 71 weeks and 87 weeks, respectively. The most frequent adverse reaction reported in the Emtricitabine/ Tenofovir disoproxil group in the iPrEx study was headache (1%). Tabulated summary of adverse reactions The adverse reactions considered at least possibly related to treatment with the components of Emtricitabine/ Tenofovir disoproxil from clinical trial and post- marketing experience in HIV-1 infected patients are listed in Table 3, below, by body system organ class and frequency.

Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness. Frequencies are defined as very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100) or rare (≥ 1/10,000 to < 1/1,000).

Table 3:

Tabulated summary of adverse reactions associated with the individual components of Emtricitabine/ Tenofovir disoproxil based on clinical study and post-marketing experience Frequency Emtricitabine Tenofovir disoproxil fumarate Blood and lymphatic system disorders: Common: neutropenia Uncommon: anaemia2 Immune system disorders: Common: allergic reaction Metabolism and nutrition disorders: Very common: Hypophosphataemia1 Common: hyperglycaemia, hypertriglyceridaemia Uncommon: hypokalaemia1 Rare: lactic acidosis Psychiatric disorders: Common: insomnia, abnormal dreams Nervous system disorders: Very common: headache dizziness Common: dizziness headache Gastrointestinal disorders: Very common: diarrhoea, nausea diarrhoea, vomiting, nausea Common: elevated amylase including elevated pancreatic amylase, elevated serum lipase, vomiting, abdominal pain, dyspepsia abdominal pain, abdominal distension, flatulence Uncommon: pancreatitis Hepatobiliary disorders: Frequency Emtricitabine Tenofovir disoproxil fumarate Common: elevated serum aspartate aminotransferase (AST) and/or elevated serum alanine aminotransferase (ALT), hyperbilirubinaemia increased transaminases Rare: hepatic steatosis, hepatitis Skin and subcutaneous tissue disorders: Very common: rash Common: vesiculobullous rash, pustular rash, maculopapular rash, rash, pruritus, urticaria, skin discolouration (increased pigmentation)2 Uncommon: Angioedema3 Rare: angioedema Musculoskeletal and connective tissue disorders: Very common: elevated creatine kinase Common: bone mineral density decreased Uncommon: rhabdomyolysis1, muscular weakness1 Rare: osteomalacia (manifested as bone pain and infrequently contributing to fractures)1,3, myopathy1 Renal and urinary disorders: Uncommon: increased creatinine, proteinuria, proximal renal tubulopathy including Fanconi syndrome Rare: renal failure (acute and chronic), acute tubular necrosis, nephritis (including acute interstitial nephritis)3, nephrogenic diabetes insipidus General disorders and administration site conditions: Very common: asthenia Common: pain, asthenia 1 This adverse reaction may occur as a consequence of proximal renal tubulopathy.

It is not considered to be causally associated with tenofovir disoproxil fumarate in the absence of this condition. 2 Anaemia was common and skin discolouration (increased pigmentation) was very common when emtricitabine was administered to paediatric patients.

3 This adverse reaction was identified through post-marketing surveillance but not observed in randomised controlled clinical trials in adults or paediatric HIV clinical trials for emtricitabine or in randomised controlled clinical trials or the tenofovir disoproxil fumarate expanded access program for tenofovir disoproxil fumarate.

The frequency category was estimated from a statistical calculation based on the total number of patients exposed to emtricitabine in randomised controlled clinical trials (n = 1,563) or tenofovir disoproxil fumarate in randomised controlled clinical trials and the expanded access program (n = 7,319).

4). Proximal renal tubulopathy generally resolved or improved after tenofovir disoproxil fumarate discontinuation. However, in some HIV-1 infected patients, declines in creatinine clearance did not completely resolve despite tenofovir disoproxil fumarate discontinuation.

4). Lactic acidosis:Cases of lactic acidosis have been reported with tenofovir disoproxil alone or in combination with otherantiretrovirals. Patients with predisposing factors such as patients with decompensated liver disease, or patientsreceiving concomitant medications known to induce lactic acidosis are at increased risk of experiencing severe lacticacidosis during tenofovir disoproxil treatment, including fatal outcomes.

4). Immune […]

1). Overall HIV-1 infection prevention strategy Emtricitabine/ Tenofovir disoproxil is not always effective in preventing the acquisition of HIV-1. The time to onset of protection after commencing Emtricitabine/ Tenofovir disoproxil is unknown.

g. consistent and correct condom use, knowledge of HIV-1 status, regular testing for other sexually transmitted infections). 3). g. at least every 3 months) using a combined antigen/antibody test while taking Emtricitabine/ Tenofovir disoproxil for pre-exposure prophylaxis.

Emtricitabine/ Tenofovir disoproxil alone does not constitute a complete regimen for the treatment of HIV-1 and HIV-1 resistance mutations have emerged in individuals with undetected HIV-1 infection who are only taking Emtricitabine/ Tenofovir disoproxil.

If clinical symptoms consistent with acute viral infection are present and recent (< 1 month) exposures to HIV-1 are suspected, use of Emtricitabine/ Tenofovir disoproxil should be delayed for at least one month and HIV-1 status reconfirmed before starting Emtricitabine/ Tenofovir disoproxil for pre-exposure prophylaxis.

Importance of adherence:

HIV-1 uninfected individuals should be counselled to strictly adhere to the recommended Emtricitabine/ Tenofovir disoproxil dosing schedule. The effectiveness of Emtricitabine/ Tenofovir disoproxil in reducing the risk of acquiring HIV-1 is strongly correlated with adherence as demonstrated by measurable drug levels in blood.

1) Patients with hepatitis B or C virus infection HIV-1 infected patients with chronic hepatitis B or C treated with antiretroviral therapy are at an increased risk for severe and potentially fatal hepatic adverse reactions. Physicians should refer to current HIV treatment guidelines for the management of HIV infection in patients co-infected with hepatitis B virus (HBV) or hepatitis C virus (HCV).

The safety and efficacy of Emtricitabine/ Tenofovir disoproxil for PrEP in patients with HBV or HCV infection has not been established. In case of concomitant antiviral therapy for hepatitis B or C, please refer also to the relevant Summary of Product Characteristics for these medicinal products.

See also under Use with ledipasvir and sofosbuvir or sofosbuvir and velpatasvir below. Tenofovir (disoproxil fumarate) is indicated for the treatment of HBV and emtricitabine has shown activity against HBV in pharmacodynamic studies but the safety and efficacy of Emtricitabine/ Tenofovir disoproxil have not been specifically established in patients with chronic HBV infection.

Discontinuation of Emtricitabine/ Tenofovir disoproxil therapy in patients infected with HBV may be associated with severe acute exacerbations of hepatitis. Patients infected with HBV who discontinue Emtricitabine/ Tenofovir disoproxil should be closely monitored with both clinical and laboratory follow-up for at least several months after stopping treatment.

If appropriate, resumption of hepatitis B therapy may be warranted. In patients with advanced liver disease or cirrhosis, treatment discontinuation is not recommended since post-treatment exacerbation of hepatitis may lead to hepatic decompensation.

Liver disease The safety and efficacy of Emtricitabine/ Tenofovir disoproxil have not been established in patients with significant underlying liver disorders. The pharmacokinetics of tenofovir has been studied in patients with hepatic impairment and no dose adjustment is required.

The pharmacokinetics of emtricitabine has not been studied in patients with hepatic impairment. 2). HIV-1infected patients with pre-existing liver dysfunction, including chronic active hepatitis, have an increased frequency of liver function abnormalities during combination antiretroviral therapy (CART) and should be monitored according to standard practice.

If there is evidence of worsening liver disease in such patients, interruption or discontinuation of treatment must be considered. Renal and bone effects in adults Renal effects Emtricitabine and tenofovir are primarily excreted by the kidneys by a combination of glomerular filtration and active tubular secretion.

8). Renal monitoring Prior to initiating Emtricitabine/ Tenofovir disoproxil for the treatment of HIV-1 infection or for use in pre-exposure prophylaxis, it is recommended that creatinine clearance is calculated in all individuals. In individuals without risk factors for renal disease, it is recommended that renal function (creatinine clearance and serum phosphate) is monitored after two to four weeks of use, after three months of use and every three to six months thereafter.

In individuals at risk for renal disease more frequent monitoring of renal function is required. 48 mmol/l) or creatinine […]

1. Use of Emtricitabine/ Tenofovir disoproxil for pre-exposure prophylaxis in individuals with unknown or positive HIV-1 status.