EMTRICITABINA/TENOFOVIR DISOPROXIL MYLAN 200mg / 245mg tablets medication leaflet

Emtricitabine/Tenofovir disoproxil Mylan 200 mg/245 mg film-coated tablets

Each film-coated tablet contains 200 mg of emtricitabine and 245 mg of tenofovir disoproxil (asmaleate).

Each tablet contains 93.6 mg lactose (as monohydrate).

For the full list of excipients, see section 6.1.

Film-coated tablet.

A light green, film-coated, capsule shaped, biconvex tablet, of dimensions 19.80 mm x 9.00 mm,debossed with ‘M’ on one side of the tablet and ‘ETD’ on the other side

Treatment of HIV-1 infection:

Emtricitabine/Tenofovir disoproxil Mylan is indicated in antiretroviral combination therapy for thetreatment of HIV-1 infected adults (see section 5.1).

Emtricitabine/Tenofovir disoproxil Mylan is also indicated for the treatment of HIV-1 infectedadolescents, with NRTI resistance or toxicities precluding the use of first line agents, (see sections 4.2,4.4 and 5.1).

Pre-exposure prophylaxis (PrEP):

Emtricitabine/Tenofovir disoproxil Mylan is indicated in combination with safer sex practices for pre-exposure prophylaxis to reduce the risk of sexually acquired HIV-1 infection in adults and adolescentsat high risk (see sections 4.2, pct. 4.4 and 5.1).

Emtricitabine/Tenofovir disoproxil Mylan should be initiated by a physician experienced in themanagement of HIV infection.

Treatment of HIV in adults and adolescents aged 12 years and older, weighing at least 35 kg: Onetablet, once daily.

Prevention of HIV in adults and adolescents aged 12 years and older, weighing at least35 kg: Onetablet, once daily.

Separate preparations of emtricitabine and tenofovir disoproxil are available for treatment of HIV-1infection if it becomes necessary to discontinue or modify the dose of one of the components of

Emtricitabine/Tenofovir disoproxil Mylan. Please refer to the Summary of Product Characteristics forthese 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 the normal dosing scheduleshould be resumed. If a dose of emtricitabine/tenofovir disoproxil is missed by more than 12 hours andit is almost time for the next dose, the missed dose should not be taken and the usual dosing scheduleshould be resumed.

If vomiting occurs within 1 hour of taking Emtricitabine/Tenofovir disoproxil Mylan, another tabletshould be taken. If vomiting occurs more than 1 hour after taking Emtricitabine/Tenofovir disoproxil

Mylan a second dose should not be taken.

No dose adjustment is required (see section 5.2).

Emtricitabine and tenofovir are eliminated by renal excretion and the exposure to emtricitabine andtenofovir increases in individuals with renal dysfunction (see sections 4.4 and 5.2).

Adults with renal impairment

Emtricitabine/tenofovir disoproxil should only be used in individuals with creatinine clearance (CrCl)<80 mL/min if the potential benefits are considered to outweigh the potential risks. See Table 1.

Table 1: Dosing recommendations in adults with renal impairment

Treatment of HIV-1 infection Pre-exposure prophylaxis

Mild renal impairment Limited data from clinical studies support Limited data from clinical studies(CrCl 50-80 mL/min) once daily dosing (see section 4.4). support once daily dosing in HIV-1 uninfected individuals with

CrCl 60-80 mL/min. Use is notrecommended in HIV-1uninfected individuals with CrCl< 60 mL/min as it has not beenstudied in this population (seesections 4.4 and 5.2).

Moderate renal Administration every 48 hours is Not recommended for use in thisimpairment (CrCl 30-49 recommended based on modelling of population.

mL/min) single-dose pharmacokinetic data foremtricitabine and tenofovir disoproxil innon-HIV infected subjects with varyingdegrees of renal impairment (see section4.4).

Severe renal impairment Not recommended because appropriate Not recommended for use in this(CrCl <30 mL/min) and dose reductions cannot be achieved with the population.

haemodialysis patients combination tablet.

Paediatrics with renal impairment:

Not recommended for use in individuals under the age of 18 years with renal impairment (seesection 4.4).

No dose adjustment is required in patients with hepatic impairment (see sections 4.4 and 5.2).

The safety and efficacy of emtricitabine/tenofovir disoproxil in children under the age of 12 yearshave not been established (see section 5.2).

Oral administration. It is preferable that Emtricitabine/Tenofovir disoproxil Mylan is taken with food.

The film-coated tablet can be disintegrated in approximately 100 mL of water, orange juice or grapejuice and taken immediately.

Hypersensitivity to the active substances or to any of the excipients listed in section 6.1.

Use for pre-exposure prophylaxis in individuals with unknown or positive HIV-1 status.

Patients with HIV-1 harbouring mutations

Emtricitabine/tenofovir disoproxil should be avoided in antiretroviral-experienced patients with HIV-1harbouring the K65R mutation (see section 5.1).

Overall HIV-1 infection prevention strategy

Emtricitabine/tenofovir disoproxil is not always effective in preventing the acquisition of HIV-1. Thetime to onset of protection after commencing emtricitabine/tenofovir disoproxil is unknown.

Emtricitabine/tenofovir disoproxil should only be used for pre-exposure prophylaxis as part of anoverall HIV-1 infection prevention strategy 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 sexuallytransmitted infections).

Risk of resistance with undetected HIV-1 infection

Emtricitabine/tenofovir disoproxil should only be used to reduce the risk of acquiring HIV-1 inindividuals confirmed to be HIV negative (see section 4.3). Individuals should be re-confirmed to be

HIV-negative at frequent intervals (e.g. at least every 3 months) using a combined antigen/antibodytest 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 infectionwho are only taking emtricitabine/tenofovir disoproxil.

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

Importance of adherence

The effectiveness of Emtricitabine/tenofovir disoproxil in reducing the risk of acquiring HIV-1 isstrongly correlated with adherence as demonstrated by measurable drug levels in blood (seesection 5.1). HIV-1 uninfected individuals should be counselled at frequent intervals to strictly adhereto the recommended Emtricitabine/tenofovir disoproxil daily dosing schedule.

Patients with hepatitis B or C virus infection

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

The safety and efficacy of emtricitabine/tenofovir disoproxil for pre-exposure prophylaxis in patientswith 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 Summaryof Product Characteristics for these medicinal products. See also under Use with ledipasvir andsofosbuvir or sofosbuvir and velpatasvir below.

Tenofovir disoproxil is indicated for the treatment of HBV and emtricitabine has shown activityagainst HBV in pharmacodynamic studies but the safety and efficacy of emtricitabine/tenofovirdisoproxil have not been specifically established in patients with chronic HBV infection.

Discontinuation of emtricitabine/tenofovir disoproxil therapy in patients infected with HBV may beassociated with severe acute exacerbations of hepatitis. Patients infected with HBV who discontinueemtricitabine/tenofovir disoproxil therapy should be closely monitored with both clinical andlaboratory follow-up for at least several months after stopping treatment. If appropriate, resumption ofhepatitis B therapy may be warranted. In patients with advanced liver disease or cirrhosis, treatmentdiscontinuation is not recommended since post-treatment exacerbation of hepatitis may lead to hepaticdecompensation.

The safety and efficacy of emtricitabine/tenofovir disoproxil have not been established in patients withsignificant underlying liver disorders. The pharmacokinetics of tenofovir has been studied in patientswith hepatic impairment and no dose adjustment is required. The pharmacokinetics of emtricitabinehas not been studied in patients with hepatic impairment. Based on minimal hepatic metabolism andthe renal route of elimination for emtricitabine, it is unlikely that a dose adjustment would be requiredfor emtricitabine/tenofovir disoproxil in patients with hepatic impairment (see sections 4.2 and 5.2).

HIV-1 infected patients with pre-existing liver dysfunction, including chronic active hepatitis, have anincreased 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 diseasein 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 glomerularfiltration and active tubular secretion. Renal failure, renal impairment, elevated creatinine,hypophosphataemia and proximal tubulopathy (including Fanconi syndrome) have been reported withthe use of tenofovir disoproxil (see section 4.8).

Renal monitoring

Prior to initiating Emtricitabine/Tenofovir disoproxil Mylan for the treatment of HIV-1 infection or foruse in pre-exposure prophylaxis, it is recommended that creatinine clearance is calculated in allindividuals.

In individuals without risk factors for renal disease, it is recommended that renal function (creatinineclearance and serum phosphate) is monitored after two to four weeks of use, after three months of useand every three to six months thereafter.

In individuals at risk for renal disease more frequent monitoring of renal function is required.

See also under Co-administration of other medicinal products below.

Renal management in HIV-1 infected patients

If serum phosphate is < 1.5 mg/dL (0.48 mmol/L) or creatinine clearance is decreased to < 50 mL/minin any patient receiving, emtricitabine/tenofovir disoproxil renal function should be re-evaluatedwithin one week, including measurements of blood glucose, blood potassium and urine glucoseconcentrations (see section 4.8, proximal tubulopathy). Consideration should be given to interruptingtreatment with emtricitabine/tenofovir disoproxil in patients with creatinine clearance decreased to< 50 mL/min or decreases in serum phosphate to < 1.0 mg/dL (0.32 mmol/L). Interrupting treatmentwith emtricitabine/tenofovir disoproxil should also be considered in case of progressive decline ofrenal function when no other cause has been identified.

Renal safety with emtricitabine/tenofovir disoproxil has only been studied to a very limited degree in

HIV-1 infected patients with impaired renal function (creatinine clearance < 80 mL/min). Doseinterval adjustments are recommended for HIV-1 infected patients with creatinine clearance30-49 mL/min (see section 4.2). Limited clinical study data suggest that the prolonged dose interval isnot optimal and could result in increased toxicity and possibly inadequate response. Furthermore, in asmall clinical study, a subgroup of patients with creatinine clearance between 50 and 60 mL/min whoreceived tenofovir disoproxil in combination with emtricitabine every 24 hours had a 2-4-fold higherexposure to tenofovir and worsening of renal function (see section 5.2). Therefore, a careful benefit-risk assessment is needed when emtricitabine/tenofovir disoproxil is used in patients with creatinineclearance < 60 mL/min, and renal function should be closely monitored. In addition, the clinicalresponse to treatment should be closely monitored in patients receiving emtricitabine/tenofovirdisoproxil at a prolonged dosing interval. The use of emtricitabine/tenofovir disoproxil is notrecommended in patients with severe renal impairment (creatinine clearance < 30 mL/min) and inpatients who require haemodialysis since appropriate dose reductions cannot be achieved with thecombination tablet (see sections 4.2 and 5.2).

Renal management in PrEP

Emtricitabine/tenofovir disoproxil has not been studied in HIV-1 uninfected individuals withcreatinine clearance < 60 mL/min and is therefore not recommended for use in this population. Ifserum phosphate is < 1.5 mg/dL (0.48 mmol/L) or creatinine clearance is decreased to < 60 mL/min inany individual receiving emtricitabine/tenofovir disoproxil for pre-exposure prophylaxis, renalfunction should be re-evaluated within one week, including measurements of blood glucose, bloodpotassium and urine glucose concentrations (see section 4.8, proximal tubulopathy). Considerationshould be given to interrupting use of emtricitabine/tenofovir disoproxil in individuals with creatinineclearance decreased to < 60 mL/min or decreases in serum phosphate to < 1.0 mg/dL (0.32 mmol/L).

Interrupting use of emtricitabine/tenofovir disoproxil should also be considered in case of progressivedecline of renal function when no other cause has been identified.

Bone effects

Bone abnormalities such as osteomalacia which can manifest as persistent or worsening bone painand, which can infrequently contribute to fractures may be associated with tenofovir disoproxilinduced proximal renal tubulopathy (see section 4.8).

If bone abnormalities are suspected or detected then appropriate consultation should be obtained.

Treatment of HIV-1 infection:

Reductions of bone mineral density (BMD) have been observed with tenofovir disoproxil inrandomized controlled clinical trials of duration up to 144 weeks in HIV or HBV-infected patients.

These BMD decreases generally improved after treatment discontinuation.

In other studies (prospective and cross-sectional), the most pronounced decreases in BMD were seenin patients treated with tenofovir disoproxil as part of a regimen containing a boosted proteaseinhibitor. Overall in view of the bone abnormalities associated with tenofovir disoproxil and thelimitations of long term data on the impact of tenofovir disoproxil on bone health and fracture risk,alternative treatment regimens should be considered for patients with osteoporosis or with a history ofbone fractures.

In clinical studies of HIV-1 uninfected individuals, small decreases in BMD were observed. In a studyof 498 men, the mean changes from baseline to week 24 in BMD ranged from -0.4% to -1.0% acrosship, spine, femoral neck and trochanter in men who received daily emtricitabine/tenofovir disoproxilprophylaxis (n = 247) vs. placebo (n = 251).

Renal and bone effects in the paediatric population

There are uncertainties associated with the long -term renal and bone effects of tenofovir disoproxilduring the treatment of HIV-1 infection in the paediatric population and on the long-term renal andbone effects of emtricitabine/tenofovir disoproxil when used for pre-exposure prophylaxis inuninfected adolescents (see section 5.1). Moreover, the reversibility of renal toxicity after cessation oftenofovir disoproxil for the treatment of HIV-1 infection or after cessation of emtricitabine/tenofovirdisoproxil for pre-exposure prophylaxis cannot be fully ascertained.

A multidisciplinary approach is recommended to weigh the benefit/risk balance ofemtricitabine/tenofovir disoproxil for the treatment of HIV-1 infection or for pre-exposureprophylaxis, decide the appropriate monitoring during treatment (including decision for treatmentwithdrawal) and consider the need for supplementation on a case by case basis.

When using emtricitabine/tenofovir disoproxil for pre-exposure prophylaxis individuals should bereassessed at each visit to ascertain whether they remain at high risk of HIV-1 infection. The risk of

HIV-1 infection should be balanced against the potential for renal and bone effects with long-term useof emtricitabine/tenofovir disoproxil.

Renal effects

Renal adverse reactions consistent with proximal renal tubulopathy have been reported in HIV 1infected paediatric patients aged 2 to < 12 years in clinical study GS US 104 0352 (see sections 4.8and 5.1).

Renal monitoring

Renal function (creatinine clearance and serum phosphate) should be evaluated prior to initiatingemtricitabine/tenofovir disoproxil for treatment of HIV-1 or for pre-exposure prophylaxis, and shouldbe monitored during use as in adults (see above).

Renal management

If serum phosphate is confirmed to be < 3.0 mg/dL (0.96 mmol/L) in any paediatric patient receiving

Emtricitabine/tenofovir disoproxil, renal function should be re-evaluated within one week, includingmeasurements of blood glucose, blood potassium and urine glucose concentrations (see section 4.8,proximal tubulopathy). If renal abnormalities are suspected or detected then consultation with anephrologist should be obtained to consider interruption of Emtricitabine/tenofovir disoproxil use.

Interrupting use of Emtricitabine/tenofovir disoproxil should also be considered in case of progressivedecline of renal function when no other cause has been identified.

Co-administration and risk of renal toxicity

The same recommendations apply as in adults (see Co-administration of other medicinal productsbelow).

The use of emtricitabine/tenofovir disoproxil is not recommended in individuals under the age of18 years with renal impairment (see section 4.2). Emtricitabine/tenofovir disoproxil should not beinitiated in paediatric patients with renal impairment and should be discontinued in paediatric patientswho develop renal impairment during emtricitabine/tenofovir disoproxil therapy.

Bone effects

Use of tenofovir disoproxil may cause a reduction in BMD. The effects of tenofovir disoproxil-associated changes in BMD on long-term bone health and future fracture risk are uncertain (seesection 5.1).

If bone abnormalities are detected or suspected during use of emtricitabine/tenofovir disoproxil in anypaediatric patient, consultation with an endocrinologist and/or nephrologist should be obtained.

An increase in weight and in levels of blood lipids and glucose may occur during antiretroviraltherapy. Such changes may in part be linked to disease control and life style. For lipids, there is insome cases evidence for a treatment effect, while for weight gain there is no strong evidence relatingthis to any particular treatment. For monitoring of blood lipids and glucose reference is made toestablished HIV treatment guidelines. Lipid disorders should be managed as clinically appropriate.

Nucleos(t)ide analogues may impact mitochondrial function to a variable degree, which is mostpronounced with stavudine, didanosine and zidovudine. There have been reports of mitochondrialdysfunction in HIV negative infants exposed in utero and/or postnatally to nucleoside analogues; thesehave predominantly concerned treatment with regimens containing zidovudine. The main adversereactions reported are haematological disorders (anaemia, neutropenia) and metabolic disorders(hyperlactatemia, hyperlipasemia). These events have often been transitory. Late onset neurologicaldisorders have been reported rarely (hypertonia, convulsion, abnormal behaviour). Whether suchneurological disorders are transient or permanent is currently unknown. These findings should beconsidered for any child exposed in utero to nucleos(t)ide analogues, who present with severe clinicalfindings of unknown etiology, particularly neurologic findings. These findings do not affect currentnational recommendations to use antiretroviral therapy in pregnant women to prevent verticaltransmission of HIV.

In HIV infected patients with severe immune deficiency at the time of institution of CART, aninflammatory reaction to asymptomatic or residual opportunistic pathogens may arise and causeserious clinical conditions, or aggravation of symptoms. Typically, such reactions have been observedwithin the first few weeks or months of initiation of CART. Relevant examples are cytomegalovirusretinitis, generalised and/or focal mycobacterial infections, and Pneumocystis jirovecii pneumonia.

Any inflammatory symptoms should be evaluated and treatment instituted when necessary.

Autoimmune disorders (such as Graves’ disease and autoimmune hepatitis) have also been reported tooccur in the setting of immune reactivation; however, the reported time to onset is more variable andthese events can occur many months after initiation of treatment.

HIV-1 infected patients receiving emtricitabine/tenofovir disoproxil or any other antiretroviral therapymay continue to develop opportunistic infections and other complications of HIV infection, andtherefore should remain under close clinical observation by physicians experienced in the treatment ofpatients with HIV associated diseases.

Although the aetiology is considered to be multifactorial (including corticosteroid use, alcoholconsumption, severe immunosuppression, higher body mass index), cases of osteonecrosis have beenreported particularly in patients with advanced HIV-disease and/or long-term exposure to CART.

Patients should be advised to seek medical advice if they experience joint aches and pain, jointstiffness or difficulty in movement.

Use of emtricitabine/tenofovir disoproxil should be avoided with concurrent or recent use of anephrotoxic medicinal product (see section 4.5). If concomitant use with nephrotoxic agents isunavoidable, renal function should be monitored weekly.

Cases of acute renal failure after initiation of high dose or multiple non-steroidal anti-inflammatorydrugs (NSAIDs) have been reported in HIV-1 infected patients treated with tenofovir disoproxil andwith risk factors for renal dysfunction. If emtricitabine/tenofovir disoproxil is co-administered with an

NSAID, renal function should be monitored adequately.

A higher risk of renal impairment has been reported in HIV-1 infected patients receiving tenofovirdisoproxil in combination with a ritonavir or cobicistat boosted protease inhibitor. Close monitoring ofrenal function is required in these patients (see section 4.5). In HIV-1 infected patients with renal riskfactors, the co-administration of tenofovir disoproxil with a boosted protease inhibitor should becarefully evaluated.

Emtricitabine/tenofovir disoproxil should not be administered concomitantly with other medicinalproducts containing emtricitabine, tenofovir disoproxil, tenofovir alafenamide, or other cytidineanalogues, such as lamivudine (see section 4.5). Emtricitabine/tenofovir disoproxil should not beadministered concomitantly with adefovir dipivoxil.

Use with ledipasvir and sofosbuvir, sofosbuvir and velpatasvir or sofosbuvir, velpatasvir andvoxilaprevir

Co-administration of tenofovir disoproxil with ledipasvir/sofosbuvir, sofosbuvir/velpatasvir orsofosbuvir/velpatasvir/voxilaprevir has been shown to increase plasma concentrations of tenofovir,especially when used together with an HIV regimen containing tenofovir disoproxil and apharmacokinetic enhancer (ritonavir or cobicistat).

The safety of tenofovir disoproxil when co-administered with ledipasvir/sofosbuvir,sofosbuvir/velpatasvir or sofosbuvir/velpatasvir/voxilaprevir and a pharmacokinetic enhancer has notbeen established. The potential risks and benefits associated with co-administration should beconsidered, particularly in patients at increased risk of renal dysfunction. Patients receivingledipasvir/sofosbuvir sofosbuvir/velpatasvir or sofosbuvir/velpatasvir/voxilaprevir concomitantly withtenofovir disoproxil and a boosted HIV protease inhibitor should be monitored for adverse reactionsrelated to tenofovir disoproxil.

Co-administration of tenofovir disoproxil and didanosine

Co-administration of tenofovir disoproxil and didanosine is not recommended (see section 4.5).

Triple nucleoside therapy

There have been reports of a high rate of virological failure and of emergence of resistance at an earlystage in HIV-1 infected patients when tenofovir disoproxil was combined with lamivudine andabacavir as well as with lamivudine and didanosine as a once daily regimen. There is close structuralsimilarity between lamivudine and emtricitabine and similarities in the pharmacokinetics andpharmacodynamics of these two agents. Therefore, the same problems may be seen ifemtricitabine/tenofovir disoproxil is administered with a third nucleoside analogue.

Emtricitabine/tenofovir disoproxil has not been studied in individuals over the age of 65 years.

Individuals over the age of 65 years are more likely to have decreased renal function, therefore cautionshould be exercised when administering emtricitabine/tenofovir disoproxil to older people.

Emtricitabine/Tenofovir disoproxil Mylan contains lactose monohydrate. Patients with rare hereditaryproblems of galactose intolerance, total lactase deficiency, or glucose-galactose malabsorption shouldnot take this medicinal product.

Interaction studies have only been performed in adults.

As emtricitabine/tenofovir disoproxil fixed-dose combination tablets contains emtricitabine andtenofovir disoproxil, any interactions that have been identified with these agents individually mayoccur with the fixed-dose combination. Interaction studies have only been performed in adults.

The steady-state pharmacokinetics of emtricitabine and tenofovir were unaffected when emtricitabineand tenofovir disoproxil were administered together versus each medicinal product dosed alone.

In vitro and clinical pharmacokinetic interaction studies have shown the potential for CYP450mediated interactions involving emtricitabine and tenofovir disoproxil with other medicinal productsis low.

Emtricitabine/tenofovir disoproxil should not be administered concomitantly with other medicinalproducts containing emtricitabine, tenofovir disoproxil, tenofovir alafenamide or other cytidineanalogues, such as lamivudine (see section 4.4). Emtricitabine/tenofovir disoproxil should not beadministered concomitantly with adefovir dipivoxil.

Didanosine: The co-administration of emtricitabine/tenofovir disoproxil and didanosine is notrecommended (see section 4.4 and Table 2).

Renally eliminated medicinal products: Since emtricitabine and tenofovir are primarily eliminated bythe kidneys, co-administration of emtricitabine/tenofovir disoproxil with medicinal products thatreduce renal function or compete for active tubular secretion (e.g. cidofovir) may increase serumconcentrations of emtricitabine, tenofovir and/or the co-administered medicinal products.

Use of emtricitabine/tenofovir disoproxil should be avoided with concurrent or recent use of anephrotoxic medicinal product. Some examples include, but are not limited to, aminoglycosides,amphotericin B, foscarnet, ganciclovir, pentamidine, vancomycin, cidofovir or interleukin-2 (seesection 4.4).

Interactions between emtricitabine/tenofovir disoproxil or its individual component(s) and othermedicinal products are listed in Table 2 below (increase is indicated as “↑”, decrease as “↓”, no changeas “↔”, twice daily as “b.i.d.” and once daily as “q.d.”). If available, 90% confidence intervals areshown in parentheses.

Table 2: Interactions between emtricitabine/tenofovir disoproxil or its individual component(s)and other medicinal products

Medicinal product by Effects on drug Recommendation concerningtherapeutic areas levels co-administration with

Mean percent emtricitabine/tenofovir disoproxilchange in AUC, (emtricitabine 200 mg, tenofovir disoproxil

Cmax, Cmin with 245 mg)90% confidenceintervals ifavailable(mechanism)

ANTI-INFECTIVES

Antiretrovirals

Protease inhibitors

Atazanavir/Ritonavir/Tenofovir Atazanavir: No dose adjustment is recommended. Thedisoproxil AUC: ↓ 25% (↓ 42 increased exposure of tenofovir could potentiate(300 mg q.d. /100 mg q.d. /245 mg to ↓ 3) tenofovir associated adverse events, includingq.d.) renal disorders. Renal function should be

Cmax: ↓ 28% (↓ 50 toclosely monitored (see section 4.4).↑ 5)

Cmin: ↓ 26% (↓ 46 to↑ 10)

Tenofovir:

AUC: ↑ 37%

Cmax: ↑ 34%

Cmin: ↑ 29%

Atazanavir/Ritonavir/Emtricitabine Interaction notstudied.

Darunavir/Ritonavir/Tenofovir Darunavir: No dose adjustment is recommended. Thedisoproxil AUC: ↔ increased exposure of tenofovir could potentiate(300 mg q.d./100 mg q.d./245 mg Cmin: ↔ tenofovir associated adverse events, includingq.d.) renal disorders. Renal function should be

Tenofovir: closely monitored (see section 4.4).

AUC: ↑ 22%

Cmin: ↑ 37%

Darunavir/Ritonavir/Emtricitabine Interaction notstudied.

Lopinavir/Ritonavir/Tenofovir Lopinavir/Ritonavir: No dose adjustment is recommended. Thedisoproxil AUC: ↔ increased exposure of tenofovir could potentiate(400 mg b.i.d./100 mg b.i.d/245 mg Cmax: ↔ tenofovir associated adverse events, includingq.d.) Cmin: ↔ renal disorders. Renal function should beclosely monitored (see section 4.4).

Tenofovir:

AUC: ↑ 32% (↑ 25to ↑ 38)

Cmax: ↔

Cmin: ↑ 51% (↑ 37 to↑ 66)

Lopinavir/Ritonavir/Emtricitabine Interaction notstudied.

NRTIs

Medicinal product by Effects on drug Recommendation concerningtherapeutic areas levels co-administration with

Mean percent emtricitabine/tenofovir disoproxilchange in AUC, (emtricitabine 200 mg, tenofovir disoproxil

Cmax, Cmin with 245 mg)90% confidenceintervals ifavailable(mechanism)

Didanosine/Tenofovir disoproxil Co-administration of Co-administration of emtricitabine/tenofovirtenofovir disoproxil disoproxil and didanosine is not recommendedand didanosine (see section 4.4).

results in a 40-60% Increased systemic exposure to didanosine mayincrease in systemic increase didanosine related adverse reactions.

exposure to Rarely, pancreatitis and lactic acidosis,didanosine. sometimes fatal, have been reported.

Didanosine/Emtricitabine Interaction not Co-administration of tenofovir disoproxil andstudied. didanosine at a dose of 400 mg daily has beenassociated with a significant decrease in CD4cell count, possibly due to an intracellularinteraction increasing phosphorylated (i.e.

active) didanosine. A decreased dosage of250 mg didanosine co-administered withtenofovir disoproxil therapy has been associatedwith reports of high rates of virological failurewithin several tested combinations for thetreatment of HIV-1 infection

Lamivudine/Tenofovir disoproxil Lamivudine: Lamivudine and emtricitabine/tenofovir

AUC: ↓ 3% (↓ 8% to disoproxil should not be administered↑ 15) concomitantly (see section 4.4).

Cmax: ↓ 24% (↓ 44 to↓ 12)

Cmin: NC

Tenofovir:

AUC: ↓ 4% (↓ 15 to↑ 8)

Cmax: ↑ 102% (↓ 96to ↑ 108)

Cmin: NC

Efavirenz/Tenofovir disoproxil Efavirenz: No dose adjustment of efavirenz is required.

AUC: ↓ 4% (↓ 7 to↓ 1)

Cmax: ↓ 4% (↓ 9 to↑ 2)

Cmin: NC

Tenofovir:

AUC: ↓ 1% (↓ 8 to↑ 6)

Cmax: ↑ 7% (↓ 6 to↑ 22)

Cmin: NC

ANTI-INFECTIVES

Hepatitis B virus (HBV) antiviral agents

Medicinal product by Effects on drug Recommendation concerningtherapeutic areas levels co-administration with

Mean percent emtricitabine/tenofovir disoproxilchange in AUC, (emtricitabine 200 mg, tenofovir disoproxil

Cmax, Cmin with 245 mg)90% confidenceintervals ifavailable(mechanism)

Adefovir dipivoxil /Tenofovir Adefovir dipivoxil: Adefovir dipivoxil and emtricitabine/tenofovirdisoproxil AUC: ↓ 11% (↓ 14 disoproxil should not be administeredto ↓ 7) concomitantly (see section 4.4).

Cmax: ↓ 7% (↓ 13 to↓ 0)

Cmin: NC

Tenofovir:

AUC: ↓ 2% (↓ 5 to↑ 0)

Cmax: ↓ 1% (↓ 7 to↑ 6)

Cmin: NC

Medicinal product by Effects on drug Recommendation concerningtherapeutic areas levels co-administration with

Mean percent emtricitabine/tenofovir disoproxilchange in AUC, (emtricitabine 200 mg, tenofovir disoproxil

Cmax, Cmin with 245 mg)90% confidenceintervals ifavailable(mechanism)

Hepatitis C virus (HCV) antiviral agents

Ledipasvir/Sofosbuvir Ledipasvir: Increased plasma concentrations of tenofovir(90 mg/400 mg q.d.) + AUC: ↑ 96% (↑ resulting from co-administration of tenofovir

Atazanavir/Ritonavir 74 to ↑ 121) disoproxil, ledipasvir/sofosbuvir and(300 mg q.d. /100 mg q.d.) + Cmax: ↑ 68% (↑ 54 atazanavir/ritonavir may increase adverse

Emtricitabine/Tenofovir disoproxilto ↑ 84)(200 mg/245 mg q.d.)1 reactions related to tenofovir disoproxil,

Cmin: ↑ 118% (↑ including renal disorders. The safety of91 to ↑ 150) tenofovir disoproxil when used withledipasvir/sofosbuvir and a pharmacokinetic

Sofosbuvir: enhancer (e.g. ritonavir or cobicistat) has not

AUC: ↔been established.

Cmax: ↔

GS-3310072:

AUC: ↔

The combination should be used with caution

Cmax: ↔with frequent renal monitoring, if other

Cmin: ↑ 42% (↑ 34alternatives are not available (see section 4.4).to ↑ 49)

AUC: ↔

Cmax: ↔

Cmin: ↑ 63% (↑ 45to ↑ 84)

AUC: ↔

Cmax: ↔

Cmin: ↑ 45% (↑ 27to ↑ 64)

AUC: ↔

Cmax: ↔

Cmin: ↔

Tenofovir:

AUC: ↔

Cmax: ↑ 47% (↑ 37 to↑ 58)

Cmin: ↑ 47% (↑ 38 to↑ 57)

Medicinal product by Effects on drug Recommendation concerningtherapeutic areas levels co-administration with

Mean percent emtricitabine/tenofovir disoproxilchange in AUC, (emtricitabine 200 mg, tenofovir disoproxil

Cmax, Cmin with 245 mg)90% confidenceintervals ifavailable(mechanism)

Ledipasvir/Sofosbuvir Ledipasvir: Increased plasma concentrations of tenofovir(90 mg/400 mg q.d.) + AUC: ↔ resulting from co-administration of tenofovir

Darunavir/Ritonavir Cmax: ↔ disoproxil, ledipasvir/sofosbuvir and(800 mg q.d. /100 mg q.d.) + Cmin: ↔ darunavir/ritonavir may increase adverse

Emtricitabine/Tenofovir disoproxil reactions related to tenofovir disoproxil,(200 mg/245 mg q.d.)1 Sofosbuvir: including renal disorders. The safety of

AUC: ↓ 27% (↓ tenofovir disoproxil when used with35 to ↓ 18) ledipasvir/sofosbuvir and a pharmacokinetic

C : ↓ 37% (↓ 48 enhancer (e.g. ritonavir or cobicistat) has notmaxbeen established.to ↓ 25)

GS-3310072:

AUC: ↔

The combination should be used with caution

Cmax: ↔with frequent renal monitoring, if other

Cmin: ↔alternatives are not available (see section 4.4).

AUC: ↔

Cmax: ↔

Cmin: ↔

AUC: ↔

Cmax: ↔

Cmin: ↑ 48% (↑ 34 to↑ 63)

AUC: ↔

Cmax: ↔

Cmin: ↔

Tenofovir:

AUC: ↑ 50% (↑ 42to ↑ 59)

Cmax: ↑ 64% (↑ 54 to↑ 74)

Cmin: ↑ 59% (↑ 49 to↑ 70)

Medicinal product by Effects on drug Recommendation concerningtherapeutic areas levels co-administration with

Mean percent emtricitabine/tenofovir disoproxilchange in AUC, (emtricitabine 200 mg, tenofovir disoproxil

Cmax, Cmin with 245 mg)90% confidenceintervals ifavailable(mechanism)

Ledipasvir/Sofosbuvir Ledipasvir: No dose adjustment is recommended. The(90 mg/400 mg q.d.) + AUC: ↓ 34% (↓ 41 increased exposure of tenofovir could potentiate

Efavirenz/Emtricitabine/Tenofovir to ↓ 25) adverse reactions associated with tenofovirdisoproxil Cmax: ↓ 34% (↓ 41 to disoproxil, including renal disorders.

(600 mg/200 mg/245 mg q.d.) ↑ 25)

Cmin: ↓ 34% (↓ 43 to Renal function should be closely monitored↑ 24) (see section 4.4).

AUC: ↔

Cmax: ↔

GS-3310072:

AUC: ↔

Cmax: ↔

Cmin: ↔

AUC: ↔

Cmax: ↔

Cmin: ↔

AUC: ↔

Cmax: ↔

Cmin: ↔

Tenofovir:

AUC: ↑ 98% (↑ 77to ↑ 123)

Cmax: ↑ 79% (↑ 56 to↑ 104)

Cmin: ↑ 163% (↑ 137to ↑ 197)

Medicinal product by Effects on drug Recommendation concerningtherapeutic areas levels co-administration with

Mean percent emtricitabine/tenofovir disoproxilchange in AUC, (emtricitabine 200 mg, tenofovir disoproxil

Cmax, Cmin with 245 mg)90% confidenceintervals ifavailable(mechanism)

Ledipasvir/Sofosbuvir Ledipasvir: No dose adjustment is recommended. The(90 mg/400 mg q.d.) + AUC: ↔ increased exposure of tenofovir could potentiate

Emtricitabine/Rilpivirine/ Cmax: ↔ adverse reactions associated with tenofovir

Tenofovir disoproxil Cmin: ↔ disoproxil, including renal disorders.

(200 mg/25 mg/245 mg q.d.)

Sofosbuvir: Renal function should be closely monitored

AUC: ↔ (see section 4.4).

Cmax: ↔

GS-3310072:

AUC: ↔

Cmax: ↔

Cmin: ↔

AUC: ↔

Cmax: ↔

Cmin: ↔

Rilpivirine:

AUC: ↔

Cmax: ↔

Cmin: ↔

Tenofovir:

AUC: ↑ 40% (↑ 31to ↑ 50)

Cmax: ↔

Cmin: ↑ 91% (↑ 74 to↑ 110)

Medicinal product by Effects on drug Recommendation concerningtherapeutic areas levels co-administration with

Mean percent emtricitabine/tenofovir disoproxilchange in AUC, (emtricitabine 200 mg, tenofovir disoproxil

Cmax, Cmin with 245 mg)90% confidenceintervals ifavailable(mechanism)

Ledipasvir/Sofosbuvir Sofosbuvir: No dose adjustment is required. The increased(90 mg/400 mg q.d.) + AUC: ↔ exposure of tenofovir could potentiate adverse

Dolutegravir (50 mg q.d.) + Cmax: ↔ reactions associated with tenofovir disoproxil,

Emtricitabine/Tenofovir disoproxil including renal disorders. Renal function(200 mg/245 mg q.d.) should be closely monitored (see section 4.4).

GS-3310072

AUC: ↔

Cmax: ↔

Cmin: ↔

Ledipasvir:

AUC: ↔

Cmax: ↔

Cmin: ↔

Dolutegravir

AUC: ↔

Cmax: ↔

Cmin: ↔

AUC: ↔

Cmax: ↔

Cmin: ↔

Tenofovir:

AUC: ↑ 65% (↑ 59to ↑ 71)

Cmax: ↑ 61% (↑ 51to ↑ 72)

Cmin: ↑ 115%(↑ 105 to ↑ 126)

Medicinal product by Effects on drug Recommendation concerningtherapeutic areas levels co-administration with

Mean percent emtricitabine/tenofovir disoproxilchange in AUC, (emtricitabine 200 mg, tenofovir disoproxil

Cmax, Cmin with 245 mg)90% confidenceintervals ifavailable(mechanism)

Sofosbuvir/Velpatasvir Sofosbuvir: Increased plasma concentrations of tenofovir(400 mg/100 mg q.d.) + AUC: ↔ resulting from co-administration of tenofovir

Atazanavir/Ritonavir Cmax: ↔ disoproxil, sofosbuvir/velpatasvir and(300 mg q.d./100 mg q.d.) + atazanavir/ritonavir may increase adverse

Emtricitabine/Tenofovir disoproxil reactions related to tenofovir disoproxil,(200 mg/245 mg q.d.) GS-3310072: including renal disorders. The safety of

AUC: ↔ tenofovir disoproxil when used with

Cmax: ↔ sofosbuvir/velpatasvir and a pharmacokinetic

Cmin: ↑ 42% (↑ 37 enhancer (e.g. ritonavir or cobicistat) has notto ↑ 49) been established.

The combination should be used with caution

with frequent renal monitoring (see

AUC: ↑ 142%section 4.4).(↑ 123 to ↑ 164)

Cmax: ↑ 55% (↑ 41to ↑ 71)

Cmin: ↑ 301%(↑ 257 to ↑ 350)

AUC: ↔

Cmax: ↔

Cmin: ↑ 39% (↑ 20to ↑ 61)

AUC: ↔

Cmax: ↔

Cmin: ↑ 29% (↑ 15to ↑ 44)

AUC: ↔

Cmax: ↔

Cmin: ↔

Tenofovir:

AUC: ↔

Cmax: ↑ 55% (↑ 43to ↑ 68)

Cmin: ↑ 39% (↑ 31to ↑ 48)

Medicinal product by Effects on drug Recommendation concerningtherapeutic areas levels co-administration with

Mean percent emtricitabine/tenofovir disoproxilchange in AUC, (emtricitabine 200 mg, tenofovir disoproxil

Cmax, Cmin with 245 mg)90% confidenceintervals ifavailable(mechanism)

Sofosbuvir/Velpatasvir Sofosbuvir: Increased plasma concentrations of tenofovir(400 mg/100 mg q.d.) + AUC: ↓ 28% (↓ 34 resulting from co-administration of tenofovir

Darunavir/Ritonavir to ↓ 20) disoproxil, sofosbuvir/velpatasvir and(800 mg q.d./100 mg q.d.) +

Cmax: ↓ 38% (↓ 46 darunavir/ritonavir may increase adverse

Emtricitabine/Tenofovir disoproxil(200 mg/245 mg q.d.) to ↓ 29) reactions related to tenofovir disoproxil,including renal disorders. The safety of

GS-3310072: tenofovir disoproxil when used with

AUC: ↔ sofosbuvir/velpatasvir and a pharmacokinetic

Cmax: ↔ enhancer (e.g. ritonavir or cobicistat) has not

Cmin: ↔ been established.

Velpatasvir: The combination should be used with caution

AUC: ↔ with frequent renal monitoring (see

Cmax: ↓ 24% (↓ 35 section 4.4).

to ↓ 11)

Cmin: ↔

AUC: ↔

Cmax: ↔

Cmin: ↔

AUC: ↔

Cmax: ↔

Cmin: ↔

AUC: ↔

Cmax: ↔

Cmin: ↔

Tenofovir:

AUC: ↑ 39% (↑ 33to ↑ 44)

Cmax: ↑ 55% (↑ 45to ↑ 66)

Cmin: ↑ 52% (↑ 45to ↑ 59)

Medicinal product by Effects on drug Recommendation concerningtherapeutic areas levels co-administration with

Mean percent emtricitabine/tenofovir disoproxilchange in AUC, (emtricitabine 200 mg, tenofovir disoproxil

Cmax, Cmin with 245 mg)90% confidenceintervals ifavailable(mechanism)

Sofosbuvir/Velpatasvir Sofosbuvir: Increased plasma concentrations of tenofovir(400 mg/100 mg q.d.) + AUC: ↓ 29% (↓ 36 resulting from co-administration of tenofovir

Lopinavir/Ritonavir to ↓ 22) disoproxil, sofosbuvir/velpatasvir and(800 mg/200 mg q.d.) +

Cmax: ↓ 41% (↓ 51 lopinavir/ritonavir may increase adverse

Emtricitabine/Tenofovir disoproxil(200 mg/245 mg q.d.) to ↓ 29) reactions related to tenofovir disoproxil,including renal disorders. The safety of

GS-3310072: tenofovir disoproxil when used with

AUC: ↔ sofosbuvir/velpatasvir and a pharmacokinetic

Cmax: ↔ enhancer (e.g. ritonavir or cobicistat) has not

Cmin: ↔ been established.

Velpatasvir: The combination should be used with caution

AUC: ↔ with frequent renal monitoring (see section

Cmax: ↓ 30% (↓ 41 4.4).

to ↓ 17)

Cmin: ↑ 63% (↑ 43to ↑ 85)

Lopinavir:

AUC: ↔

Cmax: ↔

Cmin: ↔

AUC: ↔

Cmax: ↔

Cmin: ↔

AUC: ↔

Cmax: ↔

Cmin: ↔

Tenofovir:

AUC: ↔

Cmax: ↑ 42% (↑ 27to ↑ 57)

Cmin: ↔

Medicinal product by Effects on drug Recommendation concerningtherapeutic areas levels co-administration with

Mean percent emtricitabine/tenofovir disoproxilchange in AUC, (emtricitabine 200 mg, tenofovir disoproxil

Cmax, Cmin with 245 mg)90% confidenceintervals ifavailable(mechanism)

Sofosbuvir/Velpatasvir Sofosbuvir: No dose adjustment is recommended. The(400 mg/100 mg q.d.) + AUC: ↔ increased exposure of tenofovir could potentiate

Raltegravir Cmax: ↔ adverse reactions associated with tenofovir(400 mg b.i.d) +disoproxil, including renal disorders. Renal

Emtricitabine/Tenofovir disoproxil(200 mg/245 mg q.d.) GS-3310072: function should be closely monitored (see

AUC: ↔ section 4.4).

Cmax: ↔

Cmin: ↔

AUC: ↔

Cmax: ↔

Cmin: ↔

Raltegravir:

AUC: ↔

Cmax: ↔

Cmin: ↓ 21% (↓ 58to ↑ 48)

AUC: ↔

Cmax: ↔

Cmin: ↔

Tenofovir:

AUC: ↑ 40% (↑ 34to ↑ 45)

Cmax: ↑ 46% (↑ 39to ↑ 54)

Cmin: ↑ 70% (↑ 61to ↑ 79)

Medicinal product by Effects on drug Recommendation concerningtherapeutic areas levels co-administration with

Mean percent emtricitabine/tenofovir disoproxilchange in AUC, (emtricitabine 200 mg, tenofovir disoproxil

Cmax, Cmin with 245 mg)90% confidenceintervals ifavailable(mechanism)

Sofosbuvir/Velpatasvir Sofosbuvir: Concomitant administration of(400 mg/100 mg q.d.) + AUC: ↔ sofosbuvir/velpatasvir and efavirenz is expected

Efavirenz/Emtricitabine/Tenofovir Cmax: ↑ 38% (↑ 14 to decrease plasma concentrations ofdisoproxil to ↑ 67) velpatasvir. Co-administration of(600 mg/200 mg/245 mg q.d.) sofosbuvir/velpatasvir with efavirenz-

GS-3310072: containing regimens is not recommended.

AUC: ↔

Cmax: ↔

Cmin: ↔

AUC: ↓ 53% (↓ 61to ↓ 43)

Cmax: ↓ 47% (↓ 57to ↓ 36)

Cmin: ↓ 57% (↓ 64to ↓ 48)

AUC: ↔

Cmax: ↔

Cmin: ↔

AUC: ↔

Cmax: ↔

Cmin: ↔

Tenofovir:

AUC: ↑ 81% (↑ 68to ↑ 94)

Cmax: ↑ 77% (↑ 53to ↑ 104)

Cmin: ↑ 121%(↑ 100 to ↑ 143)

Medicinal product by Effects on drug Recommendation concerningtherapeutic areas levels co-administration with

Mean percent emtricitabine/tenofovir disoproxilchange in AUC, (emtricitabine 200 mg, tenofovir disoproxil

Cmax, Cmin with 245 mg)90% confidenceintervals ifavailable(mechanism)

Sofosbuvir/Velpatasvir Sofosbuvir: No dose adjustment is recommended. The(400 mg/100 mg q.d.) + AUC: ↔ increased exposure of tenofovir could potentiate

Emtricitabine/Rilpivirine/Tenofovir Cmax: ↔ adverse reactions associated with tenofovirdisoproxil disoproxil, including renal disorders. Renal(200 mg/25 mg/245 mg q.d.) GS-3310072: function should be closely monitored (see

AUC: ↔ section 4.4).

Cmax: ↔

Cmin: ↔

AUC: ↔

Cmax: ↔

Cmin: ↔

AUC: ↔

Cmax: ↔

Cmin: ↔

Rilpivirine:

AUC: ↔

Cmax: ↔

Cmin: ↔

Tenofovir:

AUC: ↑ 40% (↑ 34to ↑ 46)

Cmax: ↑ 44% (↑ 33 to↑ 55)

Cmin: ↑ 84% (↑ 76 to↑ 92)

Medicinal product by Effects on drug Recommendation concerningtherapeutic areas levels co-administration with

Mean percent emtricitabine/tenofovir disoproxilchange in AUC, (emtricitabine 200 mg, tenofovir disoproxil

Cmax, Cmin with 245 mg)90% confidenceintervals ifavailable(mechanism)

Sofosbuvir/Velpatasvir/ Sofosbuvir: Increased plasma concentrations of tenofovir

Voxilaprevir (400 mg/100 mg/ AUC: ↔ resulting from co-administration of tenofovir100 mg+100 mg q.d.)3 + Darunavir Cmax: ↓ 30% disoproxil, sofosbuvir/velpatasvir/voxilaprevir(800 mg q.d.) + Ritonavir (100 mg Cmin: N/A and darunavir/ritonavir may increase adverseq.d.) + Emtricitabine/Tenofovir reactions related to tenofovir disoproxil,disoproxil (200 mg/245 mg q.d.) GS-3310072: including renal disorders. The safety of

AUC: ↔ tenofovir disoproxil when used with

Cmax:↔ sofosbuvir/velpatasvir/voxilaprevir and a

Cmin: N/A pharmacokinetic enhancer (e.g. ritonavir orcobicistat) has not been established.

AUC: ↔ The combination should be used with caution

Cmax: ↔ with frequent renal monitoring (see section 4.4)

Cmin: ↔

AUC: ↑ 143%

Cmax:↑ 72%

Cmin: ↑ 300%

AUC: ↔

Cmax: ↔

Cmin: ↓ 34%

AUC: ↑ 45%

Cmax: ↑ 60%

Cmin: ↔

AUC: ↔

Cmax: ↔

Cmin: ↔

Tenofovir:

AUC: ↑ 39%

Cmax: ↑ 48%

Cmin: ↑ 47%

Medicinal product by Effects on drug Recommendation concerningtherapeutic areas levels co-administration with

Mean percent emtricitabine/tenofovir disoproxilchange in AUC, (emtricitabine 200 mg, tenofovir disoproxil

Cmax, Cmin with 245 mg)90% confidenceintervals ifavailable(mechanism)

Sofosbuvir Sofosbuvir: No dose adjustment is required.

(400 mg q.d.) + AUC: ↔

Efavirenz/Emtricitabine/Tenofovir Cmax: ↓ 19% (↓ 40 todisoproxil ↑ 10)(600 mg/200 mg/245 mg q.d.)

GS-3310072:

AUC: ↔

Cmax: ↓ 23% (↓ 30 to↑ 16)

AUC: ↔

Cmax: ↔

Cmin: ↔

AUC: ↔

Cmax: ↔

Cmin: ↔

Tenofovir:

AUC: ↔

Cmax: ↑ 25% (↑ 8 to↑ 45)

Cmin: ↔

Ribavirin/Tenofovir disoproxil Ribavirin: No dose adjustment of ribavirin is required.

AUC: ↑ 26% (↑ 20to ↑ 32)

Cmax: ↓ 5% (↓ 11 to↑ 1)

Cmin: NC

Herpes virus antiviral agents

Famciclovir/Emtricitabine Famciclovir: No dose adjustment of famciclovir is required.

AUC: ↓ 9% (↓ 16 to↓ 1)

Cmax: ↓ 7% (↓ 22 to↑ 11)

Cmin: NC

AUC: ↓ 7% (↓ 13 to↓ 1)

Cmax: ↓ 11% (↓ 20 to↑ 1)

Cmin: NC

Antimycobacterials

Rifampicin /Tenofovir disoproxil Tenofovir: No dose adjustment is required.

AUC: ↓ 12% (↓ 16to ↓ 8)

Cmax: ↓ 16% (↓ 22 to↓ 10)

Cmin: ↓ 15% (↓ 12 to↓ 9)

Medicinal product by Effects on drug Recommendation concerningtherapeutic areas levels co-administration with

Mean percent emtricitabine/tenofovir disoproxilchange in AUC, (emtricitabine 200 mg, tenofovir disoproxil

Cmax, Cmin with 245 mg)90% confidenceintervals ifavailable(mechanism)

ORAL CONTRACEPTIVES

Norgestimate/Ethinyl oestradiol Norgestimate: No dose adjustment of norgestimate/ethinyl/Tenofovir disoproxil AUC: ↓ 4% (↓ 32 to oestradiol is required.

↑ 34)

Cmax: ↓ 5% (↓ 27 to↑ 24)

Cmin: NC

Ethinyl oestradiol:

AUC: ↓ 4% (↓ 9 to↑ 0)

Cmax: ↓ 6% (↓ 13 to↑ 0)

Cmin: ↓ 2% (↓ 9 to↑ 6)

IMMUNOSUPPRESSANTS

Tacrolimus/Tenofovir disoproxil Tacrolimus: No dose adjustment of tacrolimus is required.

/Emtricitabine AUC: ↑ 4% (↓ 3 to↑ 11)

Cmax: ↑ 3% (↓ 3 to↑ 9)

Cmin: NC

AUC: ↓ 5% (↓ 9 to ↓1)

Cmax: ↓ 11% (↓ 17 to↓ 5)

Cmin: NC

Tenofovir:

AUC: ↑ 6% (↓ 1 to↑ 13)

Cmax: ↑13% (↑ 1 to↑ 27)

Cmin: NC

NARCOTIC ANALGESICS

Methadone/Tenofovir disoproxil Methadone: No dose adjustment of methadone is required.

AUC: ↑ 5% (↓ 2 to↑ 13)

Cmax: ↑ 5% (↓ 3 to↑ 14)

Cmin: NC

NC = not calculated

N/A = not applicable.1 Data generated from simultaneous dosing with ledipasvir/sofosbuvir. Staggered administration (12 hours apart) providedsimilar results.2 The predominant circulating metabolite of sofosbuvir.3 Study conducted with additional voxilaprevir 100 mg to achieve voxilaprevir exposures expected in HCV-infected patients.

A large amount of data on pregnant women (more than 1,000 pregnancy outcomes) indicate nomalformations or foetal/neonatal toxicity associated with emtricitabine and tenofovir disoproxil.

Animal studies on emtricitabine and tenofovir disoproxil do not indicate reproductive toxicity (seesection 5.3). Therefore, the use of emtricitabine/tenofovir disoproxil may be considered duringpregnancy, if necessary.

Emtricitabine and tenofovir have been shown to be excreted in human milk. There is insufficientinformation on the effects of emtricitabine and tenofovir in newborns/infants. Therefore,emtricitabine/tenofovir disoproxil should not be used during breast-feeding.

In order to avoid transmission of HIV to the infant it is recommended that women living with HIV donot breast-feed their infants.

No human data on the effect of emtricitabine/tenofovir disoproxil are available. Animal studies do notindicate harmful effects of emtricitabine or tenofovir disoproxil on fertility.

No studies on the effects on the ability to drive and use machines have been performed. However,individuals should be informed that dizziness has been reported during treatment with bothemtricitabine and tenofovir disoproxil.

HIV-1 infection: The most frequently reported adverse reactions considered possibly or probablyrelated to emtricitabine and/or tenofovir disoproxil were nausea (12%) and diarrhoea (7%) in anopen-label randomised clinical study in adults (GS-01-934, see section 5.1). The safety profile ofemtricitabine and tenofovir disoproxil in this study was consistent with the previous experience withthese agents when each was administered with other antiretroviral agents.

Pre-exposure prophylaxis: No new adverse reactions to emtricitabine/tenofovir disoproxil wereidentified from two randomised placebo-controlled studies (iPrEx, Partners PrEP) in which2,830 HIV-1 uninfected adults received emtricitabine/tenofovir disoproxil once daily for pre-exposureprophylaxis. Patients were followed for a median of 71 weeks and 87 weeks, respectively. The mostfrequent adverse reaction reported in the emtricitabine/tenofovir disoproxil group in the iPrEx studywas headache (1%).

The adverse reactions considered at least possibly related to treatment with the components ofemtricitabine/tenofovir disoproxil from clinical study and post-marketing experience in HIV-1 infected patients are listed in Table 3, below, by body system organ class and frequency. Withineach 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 (≥ 1/1,000to < 1/100) or rare (≥ 1/10,000 to < 1/1,000).

Table 3: Tabulated summary of adverse reactions associated with the individual components ofemtricitabine/tenofovir disoproxil based on clinical study and post-marketing experience

Frequency Emtricitabine Tenofovir disoproxil

Common: neutropenia

Uncommon: anaemia2

Common: allergic reaction

Very common: hypophosphataemia1

Common: hyperglycaemia, hypertriglyceridaemia

Uncommon: hypokalaemia1

Rare: lactic acidosis

Common: insomnia, abnormal dreams

Very common: headache dizziness

Common: dizziness headache

Very common: diarrhoea, nausea diarrhoea, vomiting, nausea

Common: elevated amylase including elevated abdominal pain, abdominalpancreatic amylase, elevated serum distension, flatulencelipase, vomiting, abdominal pain,dyspepsia

Uncommon: pancreatitis

Common: elevated serum aspartate increased transaminasesaminotransferase (AST) and/or elevatedserum alanine aminotransferase (ALT),hyperbilirubinaemia

Rare: hepatic steatosis, hepatitis

Very common: rash

Common: vesiculobullous rash, pustular rash,maculopapular rash, rash, pruritus,urticaria, skin discolouration (increasedpigmentation)2

Uncommon: angioedema3

Rare: angioedema

Very common: elevated creatine kinase

Common bone mineral density decreased

Uncommon: rhabdomyolysis1, muscular weakness1

Rare: osteomalacia (manifested as bone painand infrequently contributing tofractures)1,3, myopathy1

Uncommon: increased creatinine, proteinuria,proximal renal tubulopathy including

Fanconi syndrome

Rare: renal failure (acute and chronic), acutetubular necrosis, nephritis(including acute interstitialnephritis)3, nephrogenic diabetesinsipidus

Frequency Emtricitabine Tenofovir disoproxil

Very common: asthenia

Common: pain, asthenia1 This adverse reaction may occur as a consequence of proximal renal tubulopathy. It is not considered to be causallyassociated with tenofovir disoproxil in the absence of this condition.2 Anaemia was common and skin discolouration (increased pigmentation) was very common when emtricitabine wasadministered to paediatric patients.3 This adverse reaction was identified through post-marketing surveillance but not observed in randomised controlledclinical studies in adults or paediatric HIV clinical studies for emtricitabine or in randomised controlled clinical studies orthe tenofovir disoproxil expanded access program for tenofovir disoproxil. The frequency category was estimated from astatistical calculation based on the total number of patients exposed to emtricitabine in randomised controlled clinicalstudies (n = 1,563) or tenofovir disoproxil in randomised controlled clinical trials and the expanded access program (n =7,319).

As emtricitabine/tenofovir disoproxil may cause renal damage, monitoring of renal function isrecommended (see section 4.4). Proximal renal tubulopathy generally resolved or improved aftertenofovir disoproxil discontinuation. However, in some HIV-1 infected patients, declines in creatinineclearance did not completely resolve despite tenofovir disoproxil discontinuation. Patients at risk ofrenal impairment (such as patients with baseline renal risk factors, advanced HIV disease, or patientsreceiving concomitant nephrotoxic medications) are at increased risk of experiencing incompleterecovery of renal function despite tenofovir disoproxil discontinuation (see section 4.4).

Lactic acidosis

Cases of lactic acidosis have been reported with tenofovir disoproxil alone or in combination withother antiretrovirals. Patients with predisposing factors such as patients with decompensated liverdisease, or patients receiving concomitant medications known to induce lactic acidosis are at increasedrisk of experiencing severe lactic acidosis during tenofovir disoproxil treatment, including fataloutcomes.

Weight and levels of blood lipids and glucose may increase during antiretroviral therapy (seesection 4.4).

In HIV infected patients with severe immune deficiency at the time of initiation of CART, aninflammatory reaction to asymptomatic or residual opportunistic infections may arise. Autoimmunedisorders (such as Graves’ disease and autoimmune hepatitis) have also been reported; however, thereported time to onset is more variable and these events can occur many months after initiation oftreatment (see section 4.4).

Cases of osteonecrosis have been reported, particularly in patients with generally acknowledged riskfactors, advanced HIV disease or long-term exposure to CART. The frequency of this is unknown (seesection 4.4).

Assessment of adverse reactions related to emtricitabine is based on experience in three paediatricstudies (n = 169) where treatment-naïve (n = 123) and treatment-experienced (n = 46) paediatric HIVinfected patients aged 4 months to 18 years were treated with emtricitabine in combination with otherantiretroviral agents. In addition to the adverse reactions reported in adults, anaemia (9.5%) and skindiscolouration (31.8%) occurred more frequently in clinical trials in paediatric patients than in adults(see section 4.8, Tabulated summary of adverse reactions).

Assessment of adverse reactions related to tenofovir disoproxil is based on two randomised trials(studies GS US 104 0321 and GS US 104 0352) in 184 HIV 1 infected paediatric patients (aged 2 to <18 years) who received treatment with tenofovir disoproxil (n = 93) or placebo/active comparator (n =91) in combination with other antiretroviral agents for 48 weeks (see section 5.1). The adversereactions observed in paediatric patients who received treatment with tenofovir disoproxil wereconsistent with those observed in clinical studies of tenofovir disoproxil in adults (see section 4.8

Tabulated summary of adverse reactions and 5.1).

Reductions in BMD have been reported in paediatric patients. In HIV 1 infected adolescents (aged 12to < 18 years), the BMD Z scores observed in subjects who received tenofovir disoproxil were lowerthan those observed in subjects who received placebo. In HIV 1 infected children (aged 2 to 15 years),the BMD Z scores observed in subjects who switched to tenofovir disoproxil were lower than thoseobserved in subjects who remained on their stavudine- or zidovudine-containing regimen (see sections4.4 and 5.1).

In study GS US 104 0352, 89 HIV-1 infected paediatric patients with a median age of 7 years (range 2to 15 years) were exposed to tenofovir disoproxil for a median of 331 weeks. Eight of the 89 patients(9.0%) discontinued study drug due to renal adverse events. Five subjects (5.6%) had laboratoryfindings clinically consistent with proximal renal tubulopathy, 4 of whom discontinued tenofovirdisoproxil therapy. Seven patients had estimated glomerular filtration rate (GFR) values between 70and 90 mL/min/1.73 m2. Among them, 3 patients experienced a clinically meaningful decline inestimated GFR during therapy which improved after discontinuation of tenofovir disoproxil.

Individuals with renal impairment: Since tenofovir disoproxil can cause renal toxicity, closemonitoring of renal function is recommended in any adults with renal impairment receivingemtricitabine/tenofovir disoproxil (see sections 4.2, pct. 4.4 and 5.2). The use of emtricitabine/tenofovirdisoproxil is not recommended in individuals under the age of 18 years with renal impairment (seesections 4.2 and 4.4).

HIV/HBV or HCV co-infected patients: The adverse reaction profile of emtricitabine and tenofovirdisoproxil in a limited number of HIV-infected patients in study GS-01-934 who were co-infectedwith HBV (n = 13) or HCV (n = 26) was similar to that observed in patients infected with HIVwithout co-infection. However, as would be expected in this patient population, elevations in AST and

ALT occurred more frequently than in the general HIV infected population.

Exacerbations of hepatitis after discontinuation of treatment: In HBV infected patients, clinical andlaboratory evidence of hepatitis have occurred after discontinuation of treatment (see section 4.4).

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

If overdose occurs the individual must be monitored for evidence of toxicity (see section 4.8), andstandard supportive treatment applied as necessary.

Up to 30% of the emtricitabine dose and approximately 10% of the tenofovir dose can be removed byhaemodialysis. It is not known whether emtricitabine or tenofovir can be removed by peritonealdialysis.

Pharmacotherapeutic group: Antiviral for systemic use; antivirals for treatment of HIV infections,combinations. ATC code: J05AR03

Emtricitabine is a nucleoside analogue of cytidine. Tenofovir disoproxil is converted in vivo totenofovir, a nucleoside monophosphate (nucleotide) analogue of adenosine monophosphate. Bothemtricitabine and tenofovir have activity that is specific to human immunodeficiency virus (HIV-1 and

HIV-2) and hepatitis B virus.

Emtricitabine and tenofovir are phosphorylated by cellular enzymes to form emtricitabine triphosphateand tenofovir diphosphate, respectively. In vitro studies have shown that both emtricitabine andtenofovir can be fully phosphorylated when combined together in cells. Emtricitabine triphosphate andtenofovir diphosphate competitively inhibit HIV-1 reverse transcriptase, resulting in DNA chaintermination.

Both emtricitabine triphosphate and tenofovir diphosphate are weak inhibitors of mammalian DNApolymerases and there was no evidence of toxicity to mitochondria in vitro and in vivo.

Synergistic antiviral activity was observed with the combination of emtricitabine and tenofovir invitro. Additive to synergistic effects were observed in combination studies with protease inhibitors,and with nucleoside and non-nucleoside analogue inhibitors of HIV reverse transcriptase.

In vitro: Resistance has been seen in vitro and in some HIV-1 infected patients due to the developmentof the M184V/I mutation with emtricitabine or the K65R mutation with tenofovir.

Emtricitabine-resistant viruses with the M184V/I mutation were cross-resistant to lamivudine, butretained sensitivity to didanosine, stavudine, tenofovir and zidovudine. The K65R mutation can alsobe selected by abacavir or didanosine and results in reduced susceptibility to these agents pluslamivudine, emtricitabine and tenofovir. Tenofovir disoproxil should be avoided in patients with

HIV-1 harbouring the K65R mutation. In addition, a K70E substitution in HIV-1 reverse transcriptasehas been selected by tenofovir and results in low-level reduced susceptibility to abacavir,emtricitabine, lamivudine and tenofovir. HIV-1 expressing three or more thymidine analogueassociated mutations (TAMs) that included either the M41L or L210W reverse transcriptase mutationshowed reduced susceptibility to tenofovir disoproxil.

In vivo treatment of HIV-1: In an open-label randomised clinical study (GS-01-934) inantiretroviral-naïve patients, genotyping was performed on plasma HIV-1 isolates from all patientswith confirmed HIV RNA > 400 copies/mL at weeks 48, 96 or 144 or at the time of early study drugdiscontinuation. As of week 144:

* The M184V/I mutation developed in 2/19 (10.5%) isolates analysed from patients in theemtricitabine/tenofovir disoproxil/efavirenz group and in 10/29 (34.5%) isolates analysed fromthe lamivudine/zidovudine/efavirenz group (p-value < 0.05, Fisher’s Exact test comparing theemtricitabine+tenofovir disoproxil group to the lamivudine/zidovudine group among allpatients).

* No virus analysed contained the K65R or K70E mutation.

* Genotypic resistance to efavirenz, predominantly the K103N mutation, developed in virus from13/19 (68%) patients in the emtricitabine/tenofovir disoproxil/efavirenz group and in virus from21/29 (72%) patients in the comparative group.

In vivo --pre-exposure prophylaxis: Plasma samples from 2 clinical studies of HIV-1 uninfectedsubjects, iPrEx and Partners PrEP, were analysed for 4 HIV-1 variants expressing amino acidsubstitutions (i.e. K65R, K70E, M184V, and M184I) that potentially confer resistance to tenofovir oremtricitabine. In the iPrEx clinical study, no HIV-1 variants expressing K65R, K70E, M184V, or

M184I were detected at the time of seroconversion among subjects who became infected with HIV-1after enrolment in the study. In 3 of 10 subjects who had acute HIV infection at study enrolment,

M184I and M184V mutations were detected in the HIV of 2 of 2 subjects in theemtricitabine/tenofovir disoproxil group and 1 of 8 subjects in the placebo group.

In the Partners PrEP clinical study, no HIV-1 variants expressing K65R, K70E, M184V, or M184Iwere detected at the time of seroconversion among subjects who became infected with HIV-1 duringthe study. In 2 of 14 subjects who had acute HIV infection at study enrolment, the K65R mutation wasdetected in the HIV of 1 of 5 subjects in the tenofovir disoproxil 245 mg group and the M184Vmutation (associated with resistance to emtricitabine) was detected in the HIV of 1 of 3 subjects in theemtricitabine/tenofovir disoproxil group.

Treatment of HIV-1 infection: In an open-label randomised clinical study (GS-01-934),antiretroviral-naïve HIV-1 infected adult patients received either a once daily regimen ofemtricitabine, tenofovir disoproxil and efavirenz (n = 255) or a fixed combination of lamivudine andzidovudine administered twice daily and efavirenz once daily (n = 254). Patients in the emtricitabineand tenofovir disoproxil group were given emtricitabine/tenofovir disoproxil and efavirenz from week96 to week 144. At baseline the randomised groups had similar median plasma HIV-1 RNA (5.02 and5.00 log10 copies/mL) and CD4 counts (233 and 241 cells/mm3). The primary efficacy endpoint for thisstudy was the achievement and maintenance of confirmed HIV-1 RNA concentrations < 400copies/mL over 48 weeks. Secondary efficacy analyses over 144 weeks included the proportion ofpatients with HIV-1 RNA concentrations < 400 or < 50 copies/mL, and change from baseline in CD4cell count.

The 48-week primary endpoint data showed that the combination of emtricitabine, tenofovir disoproxiland efavirenz provided superior antiviral efficacy as compared with the fixed combination oflamivudine and zidovudine with efavirenz as shown in Table 4. The 144 week secondary endpointdata are also presented in Table 4.

Table 4: 48- and 144-week efficacy data from study GS-01-934 in which emtricitabine, tenofovirdisoproxil and efavirenz were administered to antiretroviral-naïve patients with HIV-1 infection

GS-01-934 GS-01-934

Treatment for 48 weeks Treatment for 144 weeks

Emtricitabine+ Lamivudine+ Emtricitabine+ Lamivudine+tenofovir disoproxil zidovudine+efavirenz tenofovir disoproxil zidovudine+efavirenz+efavirenz +efavirenz*

HIV-1 RNA 84% (206/244) 73% (177/243) 71% (161/227) 58% (133/229)< 400 copies/mL(TLOVR)p-value 0.002** 0.004**% difference 11% (4% to 19%) 13% (4% to 22%)(95%CI)

HIV-1 RNA 80% (194/244) 70% (171/243) 64% (146/227) 56% (130/231)< 50 copies/mL(TLOVR)p-value 0.021** 0.082**% difference 9% (2% to 17%) 8% (-1% to 17%)(95%CI)

Mean change from +190 +158 +312 +271baseline in CD4 cellcount (cells/mm )p-value 0.002a 0.089a

Difference (95%CI) 32 (9 to 55) 41 (4 to 79)

* Patients receiving emtricitabine, tenofovir disoproxil and efavirenz were given emtricitabine/tenofovir disoproxil plusefavirenz from week 96 to 144.

** The p-value based on the Cochran-Mantel-Haenszel Test stratified for baseline CD4 cell count

TLOVR = Time to Loss of Virologic

Response a: Van Elteren Test

In a randomised clinical study (M02-418), 190 antiretroviral-naïve adults were treated once daily withemtricitabine and tenofovir disoproxil in combination with lopinavir/ritonavir given once or twicedaily. At 48 weeks, 70% and 64% of patients demonstrated HIV-1 RNA < 50 copies/mL with the onceand twice daily regimens of lopinavir/ritonavir, respectively. The mean changes in CD4 cell countfrom baseline were +185 cells/mm3 and +196 cells/mm3 respectively.

Limited clinical experience in patients co-infected with HIV and HBV suggests that treatment withemtricitabine or tenofovir disoproxil in antiretroviral combination therapy to control HIV infectionresults in a reduction in HBV DNA (3 log10 reduction or 4 to 5 log10 reduction, respectively) (seesection 4.4).

The iPrEx study (CO-US-104-0288) evaluated emtricitabine/tenofovir disoproxil or placebo in2,499 HIV-uninfected men (or transgender women) who have sex with men and who were consideredat high risk for HIV infection. Subjects were followed for 4,237 person-years. Baseline characteristicsare summarised in Table 5.

Table 5: Study population from study CO-US-104-0288 (iPrEx)

Placebo Emtricitabine/tenofovir(n = 1248) disoproxil(n = 1251)

Age (Yrs), Mean (SD) 27 (8.5) 27 (8.6)

Race, N (%)

Black/African American 97 (8) 117 (9)

White 208 (17) 223 (18)

Mixed/Other 878 (70) 849 (68)

Asian 65 (5) 62 (5)

Hispanic/Latino Ethnicity, N (%) 906 (73) 900 (72)

Sexual Risk Factors at Screening

Number of Partners Previous 12 Weeks, Mean (SD) 18 (43) 18 (35)

URAI Previous 12 Weeks, N (%) 753 (60) 732 (59)

URAI with HIV+ (or unknown status) Partner Previous 6 Mos, 1009 (81) 992 (79)

N (%)

Involved in Transactional Sex Last 6 Month, N (%) 510 (41) 517 (41)

Known HIV+ Partner Last 6 Months, N (%) 32 (3) 23 (2)

Syphilis Seroreactivity, N (%) 162/1239 (13) 164/1240 (13)

Serum Herpes Simplex Virus Type 2 Infection, N (%) 430/1243 (35) 458/1241 (37)

Urine Leukocyte Esterase Positive, N (%) 22 (2) 23 (2)

URAI = unprotected receptive anal intercourse

The incidences of HIV seroconversion overall and in the subset reporting unprotected receptive analintercourse are shown in Table 6. Efficacy was strongly correlated with adherence as assessed bydetection of plasma or intracellular drug levels in a case-control study (Table 7).

Table 6: Efficacy in study CO-US-104-0288 (iPrEx)

Placebo Emtricitabine/tenofovir P-valuea, bdisoproxilmITT Analysis

Seroconversions/N 83/1217 48/12240.002

Relative Risk Reduction (95% CI)b 42% (18%, 60%)

URAI Within 12 Weeks Prior to Screening, mITT

Analysis

Seroconversions/N 72/753 34/7320.0349

Relative Risk Reduction (95% CI)b 52% (28%, 68%)a P-values by logrank test. P-values for URAI refer to the null hypothesis that efficacy differed between subgroup strata(URAI, no URAI).b Relative risk reduction calculated for mITT based on incident seroconversion, ie, occurring post-baseline through firstpost-treatment visit (approximately 1 month after last study drug dispensation).

Table 7: Efficacy and adherence in study CO-US-104-0288 (iPrEx, matched case-controlanalysis)

Drug Drug Not Relative Risk Reduction

Cohort Detected Detected (2-sided 95% CI)a

HIV-Positive Subjects 4 (8%) 44 (92%) 94% (78%, 99%)

HIV-Negative Matched Control Subjects 63 (44%) 81 (56%) —a Relative risk reduction calculated on incident (post-baseline) seroconversion from the double-blind treatmentperiod and through the 8-week follow-up period. Only samples from subjects randomised toemtricitabine/tenofovir disoproxil were evaluated for detectable plasma or intracellular tenofovir disoproxil-

DP levels.

The Partners PrEP clinical study (CO-US-104-0380) evaluated emtricitabine/tenofovir disoproxil,tenofovir disoproxil 245 mg, or placebo in 4,758 HIV-uninfected subjects from Kenya or Uganda inserodiscordant heterosexual couples. Subjects were followed for 7,830 person-years. Baselinecharacteristics are summarised in Table 8.

Table 8: Study population from study CO-US-104-0380 (Partners PrEP)

Tenofovir

Placebo Emtricitabine/tenofovirdisoproxil(n = disoproxil245 mg1584) (n = 1579)(n = 1584)

Age (Yrs), Median (Q1, Q3) 34 (28, 33 (28, 39) 33 (28, 40)40)

Gender, N (%)

Male 963 (61) 986 (62) 1013 (64)

Female 621 (39) 598 (38) 566 (36)

Key Couple Characteristics, N (%) or Median (Q1, Q3)

Married to study partner 1552 (98) 1543 (97) 1540 (98)

Years living with study partner 7.1 (3.0, 7.0 (3.0, 13.5) 7.1 (3.0, 14.0)14.0)

Years aware of discordant status 0.4 (0.1, 0.5 (0.1, 2.0) 0.4 (0.1, 2.0)2.0)

The incidence of HIV seroconversion is shown in Table 9. The rate of HIV-1 seroconversion in maleswas 0.24/100 person-years of emtricitabine/tenofovir disoproxil exposure and the rate of HIV-1seroconversion in females was 0.95/100 person-years of emtricitabine/tenofovir disoproxil exposure.

Efficacy was strongly correlated with adherence as assessed by detection of plasma or intracellulardrug levels and was higher among substudy participants who received active adherence counsellingand as show in Table 10.

Table 9: Efficacy in study CO-US-104-0380 (Partners PrEP)

Tenofovir

Emtricitabine/tenofovir

Placebo disoproxildisoproxil245 mg

Seroconversions/Na 52/1578 17/1579 13/1576

Incidence per 100 person-years (95% CI) 1.99 (1.49, 2.62) 0.65 (0.38, 1.05) 0.50 (0.27, 0.85)

Relative Risk Reduction (95% CI) — 67% (44%, 81%) 75% (55%, 87%)a Relative risk reduction calculated for mITT cohort based on incident (post-baseline) seroconversion. Comparisons foractive study groups are made versus placebo.

Table 10: Efficacy and adherence in study CO-US-104-0380 (Partners PrEP)

Risk Estimate for HIV-1 Protection:

Detection Versus No Detection of

Number with Tenofovir Detected/ Total Tenofovir

Samples (%)

Study Drug Relative Risk

Quantification Case Cohort Reduction (95% CI) p-value

FTC/tenofovir 3/12 (25%)375/465 (81%) 90% (56%, 98%) 0.002disoproxil Groupa

Tenofovir disoproxil 6/17 (35%)a 363/437 (83%) 86% (67%, 95%) < 0.001

Group

Adherence Substudy Participantsb

Tenofovir disoproxil Relative Risk245 mg)+Emtricitabine/tenofovir Reduction (95% CI)

Adherence Substudy Placebo disoproxil p-value14/404

Seroconversions/Nb 0/745 (0%) 100% (87%, 100%) < 0.001(3.5%)a ‘Case’ = HIV seroconverter; ‘Cohort’ = 100 randomly selected subjects from each of the tenofovir disoproxil 245 mg andemtricitabine/tenofovir disoproxil groups. Only Case or Cohort samples from subjects randomised to either tenofovirdisoproxil 245 mg or emtricitabine/tenofovir disoproxil were evaluated for detectable plasma tenofovir levels.b Substudy participants received active adherence monitoring, e.g. unannounced home visits and pill counts, andcounselling to improve compliance with study drug.

The safety and efficacy of emtricitabine/tenofovir disoproxil in children under the age of 12 yearshave not been established.

Treatment of HIV-1 infection in the paediatric population

There are no clinical studies conducted with emtricitabine/tenofovir disoproxil in the paediatricpopulation with HIV-1 infection.

Clinical efficacy and safety of emtricitabine/tenofovir disoproxil was established from studies conductedwith emtricitabine and tenofovir disoproxil when given as single agents.

Studies with emtricitabine

In infants and children older than 4 months, the majority of patients taking emtricitabine achieved ormaintained complete suppression of plasma HIV 1 RNA through 48 weeks (89% achieved ≤ 400copies/mL and 77% achieved ≤ 50 copies/mL).

Studies with tenofovir disoproxil

In study GS US 104 0321, 87 HIV 1 infected treatment-experienced patients 12 to < 18 years of agewere treated with tenofovir disoproxil (n = 45) or placebo (n = 42) in combination with an optimisedbackground regimen (OBR) for 48 weeks. Due to limitations of the study, a benefit of tenofovirdisoproxil over placebo was not demonstrated based on plasma HIV 1 RNA levels at week 24. However,a benefit is expected for the adolescent population based on extrapolation of adult data and comparativepharmacokinetic data (see section 5.2).

In patients who received treatment with tenofovir disoproxil or placebo, mean lumbar spine BMD Zscore was -1.004 and -0.809, and mean total body BMD Z-score was -0.866 and -0.584, respectively, atbaseline. Mean changes at week 48 (end of double-blind phase) were -0.215 and -0.165 in lumbarspine BMD Z-score, and -0.254 and -0.179 in total body BMD Z-score for the tenofovir disoproxil andplacebo groups, respectively. The mean rate of BMD gain was less in the tenofovir disoproxil groupcompared to the placebo group. At week 48, six adolescents in the tenofovir disoproxil group and oneadolescent in the placebo group had significant lumbar spine BMD loss (defined as > 4% loss). Among28 patients receiving 96 weeks of treatment with tenofovir disoproxil, BMD Z scores declined by -0.341for lumbar spine and -0.458 for total body.

In study GS US 104 0352, 97 treatment-experienced patients 2 to < 12 years of age with stable, virologicsuppression on stavudine- or zidovudine-containing regimens were randomised to either replacestavudine or zidovudine with tenofovir disoproxil (n = 48) or continue on their original regimen (n =49) for 48 weeks. At week 48, 83% of patients in the tenofovir disoproxil treatment group and 92% ofpatients in the stavudine or zidovudine treatment group had HIV 1 RNA concentrations < 400copies/mL. The difference in the proportion of patients who maintained < 400 copies/mL at week 48was mainly influenced by the higher number of discontinuations in the tenofovir disoproxil treatmentgroup. When missing data were excluded, 91% of patients in the tenofovir disoproxil treatment groupand 94% of patients in the stavudine or zidovudine treatment group had HIV 1 RNA concentrations <400 copies/mL at week 48.

Reductions in BMD have been reported in paediatric patients. In patients who received treatment withtenofovir disoproxil, or stavudine or zidovudine, mean lumbar spine BMD Z score was 1.034 and 0.498,and mean total body BMD Z-score was 0.471 and 0.386, respectively, at baseline. Mean changes atweek 48 (end of randomised phase) were 0.032 and 0.087 in lumbar spine BMD Z score, and 0.184 and0.027 in total body BMD Z score for the tenofovir disoproxil and stavudine or zidovudine groups,respectively. The mean rate of lumbar spine bone gain at week 48 was similar between the tenofovirdisoproxil treatment group and the stavudine or zidovudine treatment group. Total body bone gain wasless in the tenofovir disoproxil treatment group compared to the stavudine or zidovudine treatmentgroup. One tenofovir disoproxil treated subject and no stavudine or zidovudine treated subjectsexperienced significant (> 4%) lumbar spine BMD loss at week 48. BMD Z scores declined by 0.012for lumbar spine and by 0.338 for total body in the 64 subjects who were treated with tenofovir disoproxilfor 96 weeks. BMD Z scores were not adjusted for height and weight.

In study GS US 104 0352, 8 out of 89 paediatric patients (9.0%) exposed to tenofovir disoproxildiscontinued study drug due to renal adverse events. Five subjects (5.6%) had laboratory findingsclinically consistent with proximal renal tubulopathy, 4 of whom discontinued tenofovir disoproxiltherapy (median tenofovir disoproxil exposure 331 weeks).

Pre-exposure prophylaxis in the paediatric population

The efficacy and safety of emtricitabine/tenofovir disoproxil for pre-exposure prophylaxis inadolescents who adhere to daily dosing is expected to be similar to that in adults at the same level ofadherence. The potential renal and bone effects with long term use of emtricitabine tenofovir disoproxilfor pre-exposure prophylaxis in adolescents are uncertain (see section 4.4).

The bioequivalence of one emtricitabine/tenofovir disoproxil fixed-combination film-coated tabletwith one emtricitabine 200 mg hard capsule and one tenofovir disoproxil 245 mg film-coated tabletwas established following single dose administration to fasting healthy subjects. Following oraladministration of emtricitabine/tenofovir disoproxil to healthy subjects, emtricitabine and tenofovirdisoproxil are rapidly absorbed and tenofovir disoproxil is converted to tenofovir. Maximumemtricitabine and tenofovir concentrations are observed in serum within 0.5 to 3.0 h of dosing in thefasted state. Administration of emtricitabine/tenofovir disoproxil with food resulted in a delay ofapproximately three quarters of an hour in reaching maximum tenofovir concentrations and increasesin tenofovir AUC and Cmax of approximately 35% and 15%, respectively, when administered with ahigh fat or light meal, compared to administration in the fasted state. In order to optimise theabsorption of tenofovir, it is recommended that emtricitabine/tenofovir disoproxil should preferably betaken with food.

Following intravenous administration, the volume of distribution of emtricitabine and tenofovir wasapproximately 1.4 L/kg and 800 mL/kg, respectively. After oral administration of emtricitabine ortenofovir disoproxil, emtricitabine and tenofovir are widely distributed throughout the body. In vitrobinding of emtricitabine to human plasma proteins was < 4% and independent of concentration overthe range of 0.02 to 200 μg/mL. In vitro protein binding of tenofovir to plasma or serum protein wasless than 0.7 and 7.2%, respectively, over the tenofovir concentration range 0.01 to 25 μg/mL.

There is limited metabolism of emtricitabine. The biotransformation of emtricitabine includesoxidation of the thiol moiety to form the 3'-sulphoxide diastereomers (approximately 9% of dose) andconjugation with glucuronic acid to form 2'-O-glucuronide (approximately 4% of dose). In vitrostudies have determined that neither tenofovir disoproxil nor tenofovir are substrates for the CYP450enzymes. Neither emtricitabine nor tenofovir inhibited in vitro drug metabolism mediated by any ofthe major human CYP450 isoforms involved in drug biotransformation. Also, emtricitabine did notinhibit uridine-5'-diphosphoglucuronyl transferase, the enzyme responsible for glucuronidation.

Emtricitabine is primarily excreted by the kidneys with complete recovery of the dose achieved inurine (approximately 86%) and faeces (approximately 14%). Thirteen percent of the emtricitabinedose was recovered in urine as three metabolites. The systemic clearance of emtricitabine averaged307 mL/min. Following oral administration, the elimination half-life of emtricitabine is approximately10 hours.

Tenofovir is primarily excreted by the kidney by both filtration and an active tubular transport systemwith approximately 70-80% of the dose excreted unchanged in urine following intravenousadministration. The apparent clearance of tenofovir averaged approximately 307 mL/min. Renalclearance has been estimated to be approximately 210 mL/min, which is in excess of the glomerularfiltration rate. This indicates that active tubular secretion is an important part of the elimination oftenofovir. Following oral administration, the elimination half-life of tenofovir is approximately 12 to18 hours.

Pharmacokinetic studies have not been performed with emtricitabine or tenofovir (administered astenofovir disoproxil) in the elderly (over 65 years of age).

Emtricitabine and tenofovir pharmacokinetics are similar in male and female patients.

No clinically important pharmacokinetic difference due to ethnicity has been identified foremtricitabine. The pharmacokinetics of tenofovir (administered as tenofovir disoproxil) have not beenspecifically studied in different ethnic groups.

Pharmacokinetic studies have not been performed with emtricitabine/tenofovir disoproxil in childrenand adolescents (under 18 years of age). Steady-state pharmacokinetics of tenofovir were evaluated in8 HIV-1 infected adolescent patients (aged 12 to < 18 years) with body weight ≥ 35 kg and in23 HIV-1 infected children aged 2 to < 12 years. Tenofovir exposure achieved in these paediatricpatients receiving oral daily doses of tenofovir disoproxil 245 mg or 6.5 mg/kg body weight tenofovirdisoproxil up to a maximum dose of 245 mg was similar to exposures achieved in adults receivingonce-daily doses of tenofovir disoproxil 245 mg. Pharmacokinetic studies have not been performedwith tenofovir disoproxil in children under 2 years. In general, the pharmacokinetics of emtricitabinein infants, children and adolescents (aged 4 months up to 18 years) are similar to those seen in adults.

The pharmacokinetics of emtricitabine and tenofovir (administered as tenofovir disoproxil) areexpected to be similar in HIV-1 infected and uninfected adolescents based on the similar exposures ofemtricitabine and tenofovir in HIV-1 infected adolescents and adults, and the similar exposures ofemtricitabine and tenofovir in HIV-1 infected and uninfected adults.

Limited pharmacokinetic data are available for emtricitabine and tenofovir after co-administration ofseparate preparations or as a fixed-dose combination in patients with renal impairment.

Pharmacokinetic parameters were mainly determined following administration of single doses ofemtricitabine 200 mg or tenofovir disoproxil 245 mg to non-HIV infected subjects with varyingdegrees of renal impairment. The degree of renal impairment was defined according to baselinecreatinine clearance (CrCl) (normal renal function when CrCl > 80 mL/min; mild impairment with

CrCl = 50-79 mL/min; moderate impairment with CrCl = 30-49 mL/min and severe impairment with

CrCl = 10-29 mL/min).

The mean (%CV) emtricitabine drug exposure increased from 12 (25%) μg*h/mL in subjects withnormal renal function, to 20 (6%) μg*h/mL, 25 (23%) μg*h/mL and 34 (6%) μg*h/mL, in subjects withmild, moderate and severe renal impairment, respectively. The mean (%CV) tenofovir drug exposureincreased from 2,185 (12%) ng*h/mL in subjects with normal renal function, to 3,064 (30%) ng*h/mL,6,009 (42%) ng*h/mL and 15,985 (45%) ng*h/mL, in subjects with mild, moderate and severe renalimpairment, respectively.

The increased dose interval for emtricitabine/tenofovir disoproxil in HIV-1 infected patients withmoderate renal impairment is expected to result in higher peak plasma concentrations and lower Cminlevels as compared to patients with normal renal function. In subjects with end-stage renal disease(ESRD) requiring haemodialysis, between dialysis drug exposures substantially increased over72 hours to 53 (19%) µg*h/mL of emtricitabine, and over 48 hours to 42,857 (29%) ng*h/mL oftenofovir.

A small clinical study was conducted to evaluate the safety, antiviral activity and pharmacokinetics oftenofovir disoproxil in combination with emtricitabine in HIV infected patients with renal impairment.

A subgroup of patients with baseline creatinine clearance between 50 and 60 mL/min, receiving oncedaily dosing, had a 2-4-fold increase in tenofovir exposure and worsening renal function.

The pharmacokinetics of emtricitabine and tenofovir (administered as tenofovir disoproxil) inpaediatric patients with renal impairment have not been studied. No data are available to make doserecommendations (see sections 4.2 and 4.4).

The pharmacokinetics of emtricitabine/tenofovir disoproxil have not been studied in subjects withhepatic impairment.

The pharmacokinetics of emtricitabine have not been studied in non-HBV infected subjects withvarying degrees of hepatic insufficiency. In general, emtricitabine pharmacokinetics in HBV infectedsubjects were similar to those in healthy subjects and in HIV infected patients.

A single 245 mg dose of tenofovir disoproxil was administered to non-HIV infected subjects withvarying degrees of hepatic impairment defined according to Child-Pugh-Turcotte (CPT) classification.

Tenofovir pharmacokinetics were not substantially altered in subjects with hepatic impairmentsuggesting that no dose adjustment is required in these subjects. The mean (%CV) tenofovir Cmax and

AUC0-∞ values were 223 (34.8%) ng/mL and 2,050 (50.8%) ng*h/mL, respectively, in normal subjectscompared with 289 (46.0%) ng/mL and 2,310 (43.5%) ng*h/mL in subjects with moderate hepaticimpairment, and 305 (24.8%) ng/mL and 2,740 (44.0%) ng*h/mL in subjects with severe hepaticimpairment.

Non-clinical data on emtricitabine reveal no special hazard for humans based on conventional studiesof safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential and toxicity toreproduction and development.

Tenofovir disoproxil

Non-clinical safety pharmacology studies on tenofovir disoproxil reveal no special hazard forhumans. Repeated dose toxicity studies in rats, dogs and monkeys at exposure levels greater than orequal to clinical exposure levels and with possible relevance to clinical use include renal and bonetoxicity and a decrease in serum phosphate concentration. Bone toxicity was diagnosed asosteomalacia (monkeys) and reduced (BMD) (rats and dogs). The bone toxicity in young adult rats anddogs occurred at exposures ≥ 5-fold the exposure in paediatric or adult patients; bone toxicity occurredin juvenile infected monkeys at very high exposures following subcutaneous dosing (≥ 40-fold theexposure in patients). Findings in the rat and monkey studies indicated that there was asubstance-related decrease in intestinal absorption of phosphate with potential secondary reduction in

BMD.

Genotoxicity studies revealed positive results in the in vitro mouse lymphoma assay, equivocal resultsin one of the strains used in the Ames test, and weakly positive results in an UDS test in primary rathepatocytes. However, it was negative in an in vivo mouse bone marrow micronucleus assay.

Oral carcinogenicity studies in rats and mice only revealed a low incidence of duodenal tumours at anextremely high dose in mice. These tumours are unlikely to be of relevance to humans.

Reproductive toxicity studies in rats and rabbits showed no effects on mating, fertility, pregnancy orfoetal parameters. However, tenofovir disoproxil reduced the viability index and weight of pups in aperi and postnatal toxicity study at maternally toxic doses.

Combination of emtricitabine and tenofovir disoproxil

Genotoxicity and repeated dose toxicity studies of one month or less with the combination of thesetwo components found no exacerbation of toxicological effects compared to studies with the separatecomponents.

Cellulose, microcrystalline

Hydroxypropyl cellulose, low substituted

Iron oxide red (E172)

Silica, colloidal anhydrous

Lactose monohydrate

Magnesium stearate

Lactose monohydrate

Hypromellose

Titanium dioxide (E171)

Triacetin

Brilliant blueFCF Aluminum lake (E133)

Iron oxide yellow (E172)

Not applicable.

2 years

Bottle pack

Use within 90 days after first opening

Do not store above 25˚C. Store in the original container in order to protect from moisture.

HDPE bottle with white opaque polypropylene screw cap or white opaque polypropylene childresistant closure with wad containing aluminium induction sealing liner and dessicant.

Pack sizes: 30 or 90 film-coated tablets and mutlipacks containing 90 (3 packs of 30) film-coatedtablets.

Cold form blister laminated with embedded desiccant layer on one side and hard tampered aluminiumfoil on the other side.

Pack sizes: 30 film-coated tablets and unit dose blister pack containing 30 x 1, 90 x 1, 100 x 1 film-coated tablets.

Cold form blister with (OPA/Aluminium foil/PVC) on one side and hard tampered aluminium foil onthe other side.

Pack sizes: 30 film-coated tablets and unit dose blister pack containing 30 x 1, 90 x 1 film-coatedtablets.

Not all pack sizes may be marketed.

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.

Mylan Pharmaceuticals Limited

Damastown Industrial Park,

Mulhuddart, Dublin 15,

DUBLIN

Ireland

EU/1/16/1133/001

EU/1/16/1133/002

EU/1/16/1133/003

EU/1/16/1133/004

EU/1/16/1133/005

EU/1/16/1133/006

EU/1/16/1133/007

EU/1/16/1133/008

EU/1/16/1133/009

EU/1/16/1133/010

Date of first authorisation: 16 December 2016

Date of latest renewal: 22 September 2021

Detailed information on this medicinal product is available on the website of the European Medicines

Agency http://www.ema.europa.eu.