EMTRIVA Oral solution Ref.[107544] Active ingredients: Emtricitabine

General

Emtricitabine is not recommended as monotherapy for the treatment of HIV infection. It must be used in combination with other antiretrovirals. Please also refer to the Summaries of Product Characteristics of the other antiretroviral medicinal products used in the combination regimen.

Co-administration of other medicinal products

Emtriva should not be taken with any other medicinal products containing emtricitabine or medicinal products containing lamivudine.

Opportunistic infections

Patients receiving emtricitabine or any other antiretroviral therapy may continue to develop opportunistic infections and other complications of HIV infection, and therefore should remain under close clinical observation by physicians experienced in the treatment of patients with HIV associated diseases.

Renal function

Emtricitabine is principally eliminated by the kidney via glomerular filtration and active tubular secretion. Emtricitabine exposure may be markedly increased in patients with severe renal insufficiency (creatinine clearance <30 ml/min) receiving daily doses of 200 mg emtricitabine as hard capsules or 240 mg as the oral solution. Consequently, either a dose interval adjustment (using Emtriva 200 mg hard capsules) or a reduction in the daily dose of emtricitabine (using Emtriva 10 mg/ml oral solution) is required in all patients with creatinine clearance <30 ml/min. The safety and efficacy of the dose interval adjustment guidelines provided in section 4.2 are based on single dose pharmacokinetic data and modelling and have not been clinically evaluated. Therefore, clinical response to treatment and renal function should be closely monitored in patients treated with emtricitabine at prolonged dosing intervals (see sections 4.2 and 5.2).

Caution should be exercised when emtricitabine is co-administered with medicinal products that are eliminated by active tubular secretion as such co-administration may lead to an increase in serum concentrations of either emtricitabine or a co-administered medicinal product, due to competition for this elimination pathway (see section 4.5).

Weight and metabolic parameters

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

Liver function

Patients with pre-existing liver dysfunction including chronic active hepatitis have an increased frequency of liver function abnormalities during CART and should be monitored according to standard practice. Patients with chronic hepatitis B or C infection treated with CART are at increased risk of experiencing severe, and potentially fatal, hepatic adverse events. In case of concomitant antiviral therapy for hepatitis B or C, please also refer to the relevant Summary of Product Characteristics for these medicinal products.

If there is evidence of exacerbations of liver disease in such patients, interruption or discontinuation of treatment must be considered.

Patients co-infected with hepatitis B virus (HBV)

Emtricitabine is active in vitro against HBV. However, limited data are available on the efficacy and safety of emtricitabine (as a 200 mg hard capsule once daily) in patients who are co-infected with HIV and HBV. The use of emtricitabine in patients with chronic HBV induces the same mutation pattern in the YMDD motif observed with lamivudine therapy. The YMDD mutation confers resistance to both emtricitabine and lamivudine.

Patients co-infected with HIV and HBV should be closely monitored with both clinical and laboratory follow-up for at least several months after stopping treatment with emtricitabine for evidence of exacerbations of hepatitis. Such exacerbations have been seen following discontinuation of emtricitabine treatment in HBV infected patients without concomitant HIV infection and have been detected primarily by serum alanine aminotransferase (ALT) elevations in addition to re-emergence of HBV DNA. In some of these patients, HBV reactivation was associated with more severe liver disease, including decompensation and liver failure. There is insufficient evidence to determine whether re-initiation of emtricitabine alters the course of post-treatment exacerbations of hepatitis. In patients with advanced liver disease or cirrhosis, treatment discontinuation is not recommended since post-treatment exacerbations of hepatitis may lead to hepatic decompensation.

Mitochondrial dysfunction following exposure in utero

Nucleos(t)ide analogues may impact mitochondrial function to a variable degree, which is most pronounced with stavudine, didanosine and zidovudine. There have been reports of mitochondrial dysfunction in HIV negative infants exposed in utero and/or postnatally to nucleoside analogues; these have predominantly concerned treatment with regimens containing zidovudine. The main adverse reactions reported are haematological disorders (anaemia, neutropenia) and metabolic disorders (hyperlactatemia, hyperlipasemia). These events have often been transitory. Late onset neurological disorders have been reported rarely (hypertonia, convulsion, abnormal behaviour). Whether such neurological disorders are transient or permanent is currently unknown. These findings should be considered for any child exposed in utero to nucleos(t)ide analogues, who present with severe clinical findings of unknown etiology, particularly neurologic findings. These findings do not affect current national recommendations to use antiretroviral therapy in pregnant women to prevent vertical transmission of HIV.

Immune Reactivation Syndrome

In HIV infected patients with severe immune deficiency at the time of institution of CART, an inflammatory reaction to asymptomatic or residual opportunistic pathogens may arise and cause serious clinical conditions, or aggravation of symptoms. Typically, such reactions have been observed within the first few weeks or months of initiation of CART. Relevant examples include cytomegalovirus retinitis, 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 to occur in the setting of immune reactivation; however, the reported time to onset is more variable and these events can occur many months after initiation of treatment.

Osteonecrosis

Although the etiology is considered to be multifactorial (including corticosteroid use, alcohol consumption, severe immunosuppression, higher body mass index), cases of osteonecrosis have been reported 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, joint stiffness or difficulty in movement.

Emtriva oral solution contains sunset yellow (E110) which may cause allergic reactions, methyl parahydroxybenzoate (E218) and propyl parahydroxybenzoate (E216) which may cause allergic reactions (possibly delayed). This medicinal product contains 38 mg of sodium per 24 mL, equivalent to 1.8% of the WHO recommended maximum daily intake of 2 g sodium for an adult.

Elderly

Emtriva has not been studied in patients over the age of 65. Elderly patients are more likely to have decreased renal function; therefore caution should be exercised when treating elderly patients with Emtriva.

Paediatric population

In addition to the adverse reactions experienced by adults, anaemia and skin discolouration occurred more frequently in clinical trials involving HIV infected paediatric patients (see section 4.8).

Interaction studies have only been performed in adults.

In vitro, emtricitabine did not inhibit metabolism mediated by any of the following human CYP450 isoforms: 1A2, 2A6, 2B6, 2C9, 2C19, 2D6 and 3A4. Emtricitabine did not inhibit the enzyme responsible for glucuronidation. Based on the results of these in vitro experiments and the known elimination pathways of emtricitabine, the potential for CYP450 mediated interactions involving emtricitabine with other medicinal products is low.

There are no clinically significant interactions when emtricitabine is co-administered with indinavir, zidovudine, stavudine, famciclovir or tenofovir disoproxil fumarate.

Emtricitabine is primarily excreted via glomerular filtration and active tubular secretion. With the exception of famciclovir and tenofovir disoproxil fumarate, the effect of co-administration of emtricitabine with medicinal products that are excreted by the renal route, or other medicinal products known to affect renal function, has not been evaluated. Co-administration of emtricitabine with medicinal products that are eliminated by active tubular secretion may lead to an increase in serum concentrations of either emtricitabine or a co-administered medicinal product due to competition for this elimination pathway.

There is no clinical experience as yet on the co-administration of cytidine analogues. Consequently, the use of emtricitabine in combination with lamivudine for the treatment of HIV infection cannot be recommended at this time.

Pregnancy

A moderate amount of data on pregnant women (between 300 and1,000 pregnancy outcomes) indicate no malformations or foetal/neonatal toxicity associated with emtricitabine. Animal studies do not indicate reproductive toxicity. The use of emtricitabine may be considered during pregnancy, if necessary.

Breast-feeding

Emtricitabine has been shown to be excreted in human milk. There is insufficient information on the effects of emtricitabine in newborns/infants. Therefore Emtriva should not be used during breastfeeding.

In order to avoid transmission of HIV to the infant it is recommended that women living with HIV do not breast-feed their infants.

Fertility

No human data on the effect of emtricitabine are available. Animal studies do not indicate harmful effects of emtricitabine on fertility.

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

Summary of the safety profile

In clinical trials of HIV infected adults, the most frequently occurring adverse reactions to emtricitabine were diarrhoea (14.0%), headache (10.2%), elevated creatine kinase (10.2%) and nausea (10.0%). In addition to the adverse reactions reported in adults, anaemia (9.5%) and skin discolouration (31.8%) occurred more frequently in clinical trials involving HIV infected paediatric patients.

Discontinuation of Emtriva therapy in patients co-infected with HIV and HBV may be associated with severe acute exacerbations of hepatitis (see section 4.4).

Tabulated summary of adverse reactions

Assessment of adverse reactions from clinical study data is based on experience in three studies in adults (n=1,479) and three paediatric studies (n=169). In the adult studies, 1,039 treatment-naïve and 440 treatment-experienced patients received emtricitabine (n=814) or comparator medicinal product (n=665) for 48 weeks in combination with other antiretroviral medicinal products.

The adverse reactions with suspected (at least possible) relationship to treatment in adults from clinical trial and post-marketing experience are listed in Table 2 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) or uncommon (≥1/1,000 to <1/100).

Table 2. Tabulated summary of adverse reactions associated with emtricitabine based on clinical study and post-marketing experience:

¹ See section 4.8, Description of selected adverse reactions for more details.
² Anaemia was common and skin discolouration (increased pigmentation) was very common when emtricitabine was administered to paediatric patients (see section 4.8, Paediatric population).
³ This adverse reaction, which was identified through post-marketing surveillance, was not observed in randomised controlled clinical trials in adults or paediatric HIV clinical trials of emtricitabine. The frequency category of uncommon was estimated from a statistical calculation based on the total number of patients exposed to emtricitabine in these clinical studies (n=1,563).

Description of selected adverse reactions

Skin discolouration (increased pigmentation)

Skin discolouration, manifested by hyperpigmentation mainly on the palms and/or soles, was generally mild, asymptomatic and of little clinical significance. The mechanism is unknown.

Metabolic parameters

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

Immune Reactivation Syndrome

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 (see section 4.4).

Osteonecrosis

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 (see section 4.4).

Paediatric population

Assessment of adverse reactions in paediatric patients from clinical study data 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 (see section 4.8, Tabulated summary of adverse reactions), the following adverse reactions were observed more frequently in paediatric patients: anaemia was common (9.5%) and skin discolouration (increased pigmentation) was very common (31.8%) in paediatric patients.

Other special population(s)

Elderly

Emtriva has not been studied in patients over the age of 65. Elderly patients are more likely to have decreased renal function, therefore caution should be exercised when treating elderly patients with Emtriva (see section 4.2).

Patients with renal impairment

Emtricitabine is eliminated by renal excretion and exposure to emtricitabine was significantly increased in patients with renal insufficiency. Dose or dose interval adjustment is required in all patients with creatinine clearance <30 ml/min (see sections 4.2, 4.4 and 5.2).

HIV/HBV co-infected patients

The adverse reaction profile in patients co-infected with HBV is similar to that observed in patients infected with HIV without co-infection with HBV. 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 HIV infected patients co-infected with HBV, exacerbations of hepatitis may occur after discontinuation of treatment (see section 4.4).

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

Not applicable.