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

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

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

Emtricitabine/Tenofovir disoproxil Mylan is also indicated for the treatment of HIV-1 infected adolescents, with NRTI resistance or toxicities precluding the use of first line agents, aged 12 to < 18 years (see section 5.1).

4.2 Posology and method of administration

Posology

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

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 individuals adults with renal impairment

Paediatrics with renal impairment:
Use of emtricitabine/tenofovir disoproxil is not recommended in HIV 1 infected paediatric patients under the age of 18 years with renal impairment (see section 4.4).

Paediatric population:
The safety and efficacy of emtricitabine/tenofovir disoproxil in children under the age of 182 years have not yet been established (see section 5.2).

Patients with hepatitis B or C virus infection

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.

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. Renal failure, renal impairment, elevated creatinine, hypophosphataemia and proximal tubulopathy (including Fanconi syndrome) have been reported with the use of tenofovir disoproxil (see section 4.8).

Renal monitoring:

Renal management in HIV-1 infected patients:

Emtricitabine/tenofovir disoproxil for Renal management in PrEP:

Renal and bone effects in the paediatric population

There are uncertainties associated with the long term effects of tenofovir disoproxil bone and renal toxicity. Moreover, the reversibility of renal toxicity cannot be fully ascertained. Therefore, a multidisciplinary approach is recommended to adequately weigh on a case by case basis the benefit/risk balance of treatment, decide the appropriate monitoring during treatment (including decision for treatment withdrawal) and consider the need for supplementation.

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

Renal monitoring
Renal function (creatinine clearance and serum phosphate) should be evaluated prior to treatment, and monitored during treatment as in HIV 1 infected 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, including measurements 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 a nephrologist should be obtained to consider interruption of treatment. Interrupting treatment with emtricitabine/tenofovir disoproxil should also be considered in case of progressive decline 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 products below).

Renal impairment
The use of emtricitabine/tenofovir disoproxil is not recommended in paediatric patients with renal impairment (see section 4.2). Emtricitabine/tenofovir disoproxil should not be initiated in paediatric patients with renal impairment and should be discontinued in paediatric patients who develop renal impairment during emtricitabine/tenofovir disoproxil therapy.

Bone effects
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 currently unknown (see section 5.1).

If bone abnormalities are detected or suspected in paediatric patients, consultation with an endocrinologist and/or nephrologist should be obtained.

Use with ledipasvir and sofosbuvir or sofosbuvir and velpatasvir

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

 

The safety of tenofovir disoproxil when co-administered with ledipasvir/sofosbuvir or sofosbuvir/velpatasvir and a pharmacokinetic enhancer has not been established. The potential risks and benefits associated with co-administration should be considered, particularly in patients at increased risk of renal dysfunction. Patients receiving ledipasvir/sofosbuvir or sofosbuvir/velpatasvir concomitantly with tenofovir disoproxil and a boosted HIV protease inhibitor should be monitored for adverse reactions related to tenofovir disoproxil.

4.5 Interaction with other medicinal products and other forms of interaction

Interaction studies have only been performed in adults.

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

Extensive changes to Table 2

4.8 Undesirable effects

Summary of the safety profile

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

Paediatric population

Emtricitabine/tenofovir disoproxil is not recommended in this population (see section 4.2).
Assessment of adverse reactions related to emtricitabine is based on experience in three paediatric studies (n = 169) where treatment-naïve (n = 123) and treatment-experienced (n = 46) paediatric HIV infected patients aged 4 months to 18 years were treated with emtricitabine in combination with other antiretroviral agents. In addition to the adverse reactions reported in adults, anaemia (9.5%) and skin discolouration (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 adverse reactions observed in paediatric patients who received treatment with tenofovir disoproxil were consistent 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 12 to < 18 years), the BMD Z scores observed in subjects who received tenofovir disoproxil were lower than 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 those observed in subjects who remained on their stavudine- or zidovudine-containing regimen (see sections 4.4 and 5.1).

In study GS US 104 0352, 89 paediatric patients with a median age of 7 years (range 2 to 15 years) were exposed to tenofovir disoproxil for a median of 313 weeks. Four of the 89 patients discontinued due to adverse reactions consistent with proximal renal tubulopathy. Seven patients had estimated glomerular filtration rate (GFR) values between 70 and 90 mL/min/1.73 m2. Among them, two patients experienced a clinically meaningful decline in estimated GFR during therapy which improved after discontinuation of tenofovir disoproxil.

Other special populations

Individuals with renal impairment: Since tenofovir disoproxil can cause renal toxicity, close monitoring of renal function is recommended in any individual adults with renal impairment treated with emtricitabine/tenofovir disoproxil (see sections 4.2, 4.4 and 5.2). The use of emtricitabine/tenofovir disoproxil is not recommended in paediatric patients with renal impairment (see sections 4.2 and 4.4).

Clinical data

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 of emtricitabine, tenofovir disoproxil and efavirenz (n = 255) or a fixed combination of lamivudine and zidovudine administered twice daily and efavirenz once daily (n = 254).

Paediatric population

There are no clinical studies conducted with emtricitabine/tenofovir disoproxil in the paediatric population.

Clinical efficacy and safety of emtricitabine/tenofovir disoproxil was established from studies conducted with 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 or maintained complete suppression of plasma HIV 1 RNA through 48 weeks (89% achieved ≤ 400 copies/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 age were treated with tenofovir disoproxil (n = 45) or placebo (n = 42) in combination with an optimised background regimen (OBR) for 48 weeks. Due to limitations of the study, a benefit of tenofovir disoproxil 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 comparative pharmacokinetic data (see section 5.2).

In patients who received treatment with tenofovir disoproxil or placebo, mean lumbar spine BMD Z score was -1.004 and -0.809, and mean total body BMD Z-score was -0.866 and -0.584, respectively, at baseline. Mean changes at week 48 (end of double-blind phase) were -0.215 and -0.165 in lumbar spine BMD Z-score, and -0.254 and -0.179 in total body BMD Z-score for the tenofovir disoproxil and placebo groups, respectively. The mean rate of BMD gain was less in the tenofovir disoproxil group compared to the placebo group. At week 48, six adolescents in the tenofovir disoproxil group and one adolescent in the placebo group had significant lumbar spine BMD loss (defined as > 4% loss). Among 28 patients receiving 96 weeks of treatment with tenofovir disoproxil, BMD Z scores declined by -0.341 for 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, virologic suppression on stavudine- or zidovudine-containing regimens were randomised to either replace stavudine 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% of patients in the stavudine or zidovudine treatment group had HIV 1 RNA concentrations < 400 copies/mL. The difference in the proportion of patients who maintained < 400 copies/mL at week 48 was mainly influenced by the higher number of discontinuations in the tenofovir disoproxil treatment group. When missing data were excluded, 91% of patients in the tenofovir disoproxil treatment group and 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 with tenofovir 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 at week 48 (end of randomised phase) were 0.032 and 0.087 in lumbar spine BMD Z score, and 0.184 and 0.027 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 tenofovir disoproxil treatment group and the stavudine or zidovudine treatment group. Total body bone gain was less in the tenofovir disoproxil treatment group compared to the stavudine or zidovudine treatment group. One tenofovir disoproxil treated subject and no stavudine or zidovudine treated subjects experienced significant (> 4%) lumbar spine BMD loss at week 48. BMD Z scores declined by 0.012 for lumbar spine and by 0.338 for total body in the 64 subjects who were treated with tenofovir disoproxil for 96 weeks. BMD Z scores were not adjusted for height and weight.

In study GS US 104 0352, 4 out of 89 paediatric patients exposed to tenofovir disoproxil discontinued due to adverse reactions consistent with proximal renal tubulopathy (median tenofovir disoproxil exposure 104 weeks).

The safety and efficacy of emtricitabine/tenofovir disoproxil in children under the age of 182 years in the treatment of HIV 1 infection have not been established. The European Medicines Agency has deferred the obligation to submit the results of studies with emtricitabine/tenofovir disoproxil in one or more subsets of the paediatric population in the treatment of HIV 1 infection and for pre-exposure prophylaxis (see section 4.2 for information on paediatric use).

Renal impairment

The pharmacokinetics of emtricitabine and tenofovir in paediatric patients with renal impairment have not been studied. No data are available to make dose recommendations (see sections 4.2 and 4.4).

None provided