Chemical formula: C₃₁H₄₄FN₈O₁₇PS Molecular mass: 882.227 g/mol
Tenofovir disoproxil and Emtricitabine interacts in the following cases:
Emtricitabine and tenofovir are eliminated by renal excretion and the exposure to emtricitabine and tenofovir increases in individuals with renal dysfunction.
Emtricitabine/tenofovir disoproxil combination 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.
Dosing recommendations in adults with renal impairment:
| Treatment of HIV-1 infection | Pre-exposure prophylaxis | |
|---|---|---|
| Mild renal impairment (CrCl 50-80 mL/min) | Limited data from clinical studies support once daily dosing. | Limited data from clinical studies support once daily dosing in HIV-1 uninfected individuals with CrCl 60-80 mL/min. Use is not recommended in HIV-1 uninfected individuals with CrCl <60 mL/min as it has not been studied in this population. |
| Moderate renal impairment (CrCl 30-49 mL/min) | Administration every 48 hours is recommended based on modelling of single-dose pharmacokinetic data for emtricitabine and tenofovir disoproxil in non-HIV infected subjects with varying degrees of renal impairment. | Not recommended for use in this population. |
| Severe renal impairment (CrCl <30 mL/min) and haemodialysis patients | Not recommended because appropriate dose reductions cannot be achieved with the combination tablet. | Not recommended for use in this population. |
Not recommended for use in individuals under the age of 18 years with renal impairment.
The safety and efficacy of emtricitabine/tenofovir disoproxil have not been established in patients with significant underlying liver disorders. The pharmacokinetics of tenofovir has been studied in patients with hepatic impairment and no dose adjustment is required. The pharmacokinetics of emtricitabine has not been studied in patients with hepatic impairment. Based on minimal hepatic metabolism and the renal route of elimination for emtricitabine, it is unlikely that a dose adjustment would be required for emtricitabine/tenofovir disoproxil in patients with hepatic impairment.
HIV-1 infected patients with pre-existing liver dysfunction, including chronic active hepatitis, have an increased frequency of liver function abnormalities during combination antiretroviral therapy (CART) and should be monitored according to standard practice. If there is evidence of worsening liver disease in such patients, interruption or discontinuation of treatment must be considered.
HIV-1 infected patients with chronic hepatitis B or C treated with antiretroviral therapy are at an increased risk for severe and potentially fatal hepatic adverse reactions. Physicians should refer to current HIV treatment guidelines for the management of HIV infection in patients co-infected with hepatitis B virus (HBV) or hepatitis C virus (HCV).
The safety and efficacy of emtricitabine/tenofovir disoproxil for pre-exposure prophylaxis in patients with HBV or HCV infection has not been established.
In case of concomitant antiviral therapy for hepatitis B or C, please refer also to the relevant Summary of Product Characteristics for these medicinal products.
Tenofovir disoproxil is indicated for the treatment of HBV and emtricitabine has shown activity against HBV in pharmacodynamic studies but the safety and efficacy of emtricitabine/tenofovir disoproxil have not been specifically established in patients with chronic HBV infection.
Discontinuation of emtricitabine/tenofovir disoproxil therapy in patients infected with HBV may be associated with severe acute exacerbations of hepatitis. Patients infected with HBV who discontinue emtricitabine/tenofovir disoproxil should be closely monitored with both clinical and laboratory follow-up for at least several months after stopping treatment. If appropriate, resumption of hepatitis B therapy may be warranted. In patients with advanced liver disease or cirrhosis, treatment discontinuation is not recommended since post-treatment exacerbation of hepatitis may lead to hepatic decompensation.
Emtricitabine/tenofovir disoproxil should be avoided in antiretroviral-experienced patients with HIV-1 harbouring the K65R mutation.
A large amount of data on pregnant women (more than 1,000 pregnancy outcomes) indicate no malformations or foetal/neonatal toxicity associated with emtricitabine and tenofovir disoproxil. Animal studies on emtricitabine and tenofovir disoproxil do not indicate reproductive toxicity. Therefore the use of emtricitabine/tenofovir disoproxil may be considered during pregnancy, if necessary.
Emtricitabine and tenofovir have been shown to be excreted in human milk. There is insufficient information on the effects of emtricitabine and tenofovir in 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 do not breast-feed their infants.
No human data on the effect of emtricitabine/tenofovir disoproxil are available. Animal studies do not indicate 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 both emtricitabine and tenofovir disoproxil.
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). 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.
No new adverse reactions to emtricitabine/tenofovir disoproxil were identified from two randomised placebo-controlled studies (iPrEx, Partners PrEP) in which 2,830 HIV-1 uninfected adults received emtricitabine/tenofovir disoproxil once daily for pre-exposure prophylaxis. Patients were followed for a median of 71 weeks and 87 weeks, respectively. The most frequent adverse reaction reported in the emtricitabine/tenofovir disoproxil group in the iPrEx study was headache (1%).
The adverse reactions considered at least possibly related to treatment with the components of emtricitabine/tenofovir disoproxil from clinical study and post-marketing experience in HIV-1 infected patients are listed in the table below by body system organ class and frequency. Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness. Frequencies are defined as very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100) or rare (≥1/10,000 to <1/1,000).
Tabulated summary of adverse reactions associated with the individual components of emtricitabine/tenofovir disoproxil based on clinical study and post-marketing experience:
| Frequency | Emtricitabine | Tenofovir disoproxil |
|---|---|---|
| Blood and lymphatic system disorders | ||
| Common: | neutropenia | |
| Uncommon: | anaemia2 | |
| Immune system disorders | ||
| Common: | allergic reaction | |
| Metabolism and nutrition disorders | ||
| Very common: | hypophosphataemia1 | |
| Common: | hyperglycaemia, hypertriglyceridaemia | |
| Uncommon: | hypokalaemia1 | |
| Rare: | lactic acidosis | |
| Psychiatric disorders | ||
| Common: | insomnia, abnormal dreams | |
| Nervous system disorders | ||
| Very common: | headache | dizziness |
| Common: | dizziness | headache |
| Gastrointestinal disorders | ||
| Very common: | diarrhoea, nausea | diarrhoea, vomiting, nausea |
| Common: | elevated amylase including elevated pancreatic amylase, elevated serum lipase, vomiting, abdominal pain, dyspepsia | abdominal pain, abdominal distension, flatulence |
| Uncommon: | pancreatitis | |
| Hepatobiliary disorders | ||
| Common: | elevated serum aspartate aminotransferase (AST) and/or elevated serum alanine aminotransferase (ALT), hyperbilirubinaemia | increased transaminases |
| Rare: | hepatic steatosis, hepatitis | |
| Skin and subcutaneous tissue disorders | ||
| Very common: | rash | |
| Common: | vesiculobullous rash, pustular rash, maculopapular rash, rash, pruritus, urticaria, skin discolouration (increased pigmentation)2 | |
| Uncommon: | angioedema3 | |
| Rare: | angioedema | |
| Musculoskeletal and connective tissue disorders | ||
| Very common: | elevated creatine kinase | |
| Uncommon: | rhabdomyolysis1, muscular weakness1 | |
| Rare: | osteomalacia (manifested as bone pain and infrequently contributing to fractures)1,3, myopathy1 | |
| Renal and urinary disorders | ||
| Uncommon: | increased creatinine, proteinuria, proximal renal tubulopathy including Fanconi syndrome | |
| Rare: | renal failure (acute and chronic), acute tubular necrosis, nephritis (including acute interstitial nephritis)3, nephrogenic diabetes insipidus | |
| General disorders and administration site conditions | ||
| Very common: | asthenia | |
| Common: | pain, asthenia | |
1 This adverse reaction may occur as a consequence of proximal renal tubulopathy. It is not considered to be causally associated with tenofovir disoproxil in the absence of this condition.
^26 Anaemia was common and skin discolouration (increased pigmentation) was very common when emtricitabine was administered to paediatric patients.
3 This adverse reaction was identified through post-marketing surveillance but not observed in randomised controlled clinical studies in adults or paediatric HIV clinical studies for emtricitabine or in randomised controlled clinical studies or the tenofovir disoproxil expanded access program for tenofovir disoproxil. The frequency category was estimated from a statistical calculation based on the total number of patients exposed to emtricitabine in randomised controlled clinical studies (n=1,563) or tenofovir disoproxil in randomised controlled clinical studies and the expanded access program (n=7,319).
As emtricitabine/tenofovir disoproxil may cause renal damage monitoring of renal function is recommended. Proximal renal tubulopathy generally resolved or improved after tenofovir disoproxil discontinuation. However, in some HIV-1 infected patients, declines in creatinine clearance did not completely resolve despite tenofovir disoproxil discontinuation. Patients at risk of renal impairment (such as patients with baseline renal risk factors, advanced HIV disease, or patients receiving concomitant nephrotoxic medications) are at increased risk of experiencing incomplete recovery of renal function despite tenofovir disoproxil discontinuation.
Cases of lactic acidosis have been reported with tenofovir disoproxil alone or in combination with other antiretrovirals. Patients with predisposing factors such as patients with decompensated liver disease, or patients receiving concomitant medications known to induce lactic acidosis are at increased risk of experiencing severe lactic acidosis during tenofovir disoproxil treatment, including fatal outcomes.
Weight and levels of blood lipids and glucose may increase during antiretroviral therapy.
In HIV infected patients with severe immune deficiency at the time of initiation of CART, an inflammatory reaction to asymptomatic or residual opportunistic infections may arise. Autoimmune disorders (such as Graves' disease and autoimmune hepatitis) have also been reported; however, the reported time to onset is more variable and these events can occur many months after initiation of treatment.
Cases of osteonecrosis have been reported, particularly in patients with generally acknowledged risk factors, advanced HIV disease or long-term exposure to CART. The frequency of this is unknown.
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.
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. 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.
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.
In study GS-US-104-0352, 89 HIV-1 infected paediatric patients with a median age of 7 years (range 2 to 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 laboratory findings clinically consistent with proximal renal tubulopathy, 4 of whom discontinued tenofovir disoproxil therapy. Seven patients had estimated glomerular filtration rate (GFR) values between 70 and 90 mL/min/1.73 m². Among them, 3 patients experienced a clinically meaningful decline in estimated GFR during therapy which improved after discontinuation of tenofovir disoproxil.
Since tenofovir disoproxil can cause renal toxicity, close monitoring of renal function is recommended in any adults with renal impairment receiving emtricitabine/tenofovir disoproxil. The use of emtricitabine/tenofovir disoproxil is not recommended in individuals under the age of 18 years with renal impairment.
The adverse reaction profile of emtricitabine and tenofovir disoproxil in a limited number of HIV-infected patients in study GS-01-934 who were co-infected with HBV (n=13) or HCV (n=26) was similar to that observed in patients infected with HIV without 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.
In HBV infected patients, clinical and laboratory evidence of hepatitis have occurred after discontinuation of treatment.
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