4.1. Therapeutic indications

Efavirenz/Emtricitabine/Tenofovir disoproxil is a fixed-dose combination of efavirenz, emtricitabine and tenofovir disoproxil. It is indicated for the treatment of human immunodeficiency virus-1 (HIV-1) infection in adults aged 18 years and over with virologic suppression to HIV-1 RNA levels of < 50 copies/ml on their current combination antiretroviral therapy for more than three months. Patients must not have experienced virological failure on any prior antiretroviral therapy and must be known not to have harboured virus strains with mutations conferring significant resistance to any of the three components contained in Efavirenz/Emtricitabine/Tenofovir disoproxil prior to initiation of their first antiretroviral treatment regimen (see sections 4.4 and 5.1).

The demonstration of the benefit of the fixed-dose combination of efavirenz/emtricitabine/tenofovir disoproxil is primarily based on 48-week data from a clinical study in which patients with stable virologic suppression on a combination antiretroviral therapy changed to the fixed-dose combination of efavirenz/emtricitabine/tenofovir disoproxil (see section 5.1). No data are currently available from clinical studies with the fixed-dose combination of efavirenz/emtricitabine/tenofovir disoproxil in treatment-naïve or in heavily pretreated patients.

No data are available to support the combination of Efavirenz/Emtricitabine/Tenofovir disoproxil and other antiretroviral agents.

4.2. Posology and method of administration

Therapy should be initiated by a physician experienced in the management of HIV infection.

Posology

Adults

The recommended dose of Efavirenz/Emtricitabine/Tenofovir disoproxil is one tablet taken orally once daily.

If a patient misses a dose of Efavirenz/Emtricitabine/Tenofovir disoproxil within 12 hours of the time it is usually taken, the patient should take Efavirenz/Emtricitabine/Tenofovir disoproxil as soon as possible and resume the normal dosing schedule. If a patient misses a dose of Efavirenz/Emtricitabine/Tenofovir disoproxil by more than 12 hours and it is almost time for the next dose, the patient should not take the missed dose and simply resume the usual dosing schedule.

If the patient vomits within 1 hour of taking Efavirenz/Emtricitabine/Tenofovir disoproxil, another tablet should be taken. If the patient vomits more than 1 hour after taking Efavirenz/Emtricitabine/Tenofovir disoproxil he/she does not need to take another dose.

It is recommended that Efavirenz/Emtricitabine/Tenofovir disoproxil be taken on an empty stomach since food may increase efavirenz exposure and may lead to an increase in the frequency of adverse reactions (see sections 4.4 and 4.8). In order to improve the tolerability to efavirenz with respect to undesirable effects on the nervous system, bedtime dosing is recommended (see section 4.8).

It is anticipated that tenofovir exposure (AUC) will be approximately 30% lower following administration of Efavirenz/Emtricitabine/Tenofovir disoproxil on an empty stomach as compared to the individual component tenofovir disoproxil when taken with food (see section 5.2). Data on the clinical translation of the decrease in pharmacokinetic exposure are not available. In virologically suppressed patients, the clinical relevance of this reduction can be expected to be limited (see section 5.1).

Where discontinuation of therapy with one of the components of Efavirenz/Emtricitabine/Tenofovir disoproxil is indicated or where dose modification is necessary, separate preparations of efavirenz, emtricitabine and tenofovir disoproxil are available. Please refer to the Summary of Product Characteristics for these medicinal products.

If therapy with Efavirenz/Emtricitabine/Tenofovir disoproxil is discontinued, consideration should be given to the long half-life of efavirenz (see section 5.2) and long intracellular half-lives of emtricitabine and tenofovir. Because of interpatient variability in these parameters and concerns regarding development of resistance, HIV treatment guidelines should be consulted, also taking into consideration the reason for discontinuation.

Dose adjustment: If Efavirenz/Emtricitabine/Tenofovir disoproxil is co-administered with rifampicin to patients weighing 50 kg or more, an additional 200 mg/day (800 mg total) of efavirenz may be considered (see section 4.5).

Special populations

Elderly

Efavirenz/Emtricitabine/Tenofovir disoproxil should be administered with caution to elderly patients (see section 4.4).

Renal impairment

Efavirenz/Emtricitabine/Tenofovir disoproxil is not recommended for patients with moderate or severe renal impairment (creatinine clearance (CrCl) < 50 ml/min). Patients with moderate or severe renal impairment require dose interval adjustment of emtricitabine and tenofovir disoproxil that cannot be achieved with the combination tablet (see sections 4.4 and 5.2).

Hepatic impairment

The pharmacokinetics of the fixed-dose combination of efavirenz/emtricitabine/tenofovir disoproxil have not been studied in patients with hepatic impairment. Patients with mild liver disease (Child-Pugh-Turcotte (CPT), Class A) may be treated with the normal recommended dose of Efavirenz/Emtricitabine/Tenofovir disoproxil (see sections 4.3, 4.4 and 5.2). Patients should be monitored carefully for adverse reactions, especially nervous system symptoms related to efavirenz (see sections 4.3 and 4.4).

If Efavirenz/Emtricitabine/Tenofovir disoproxil is discontinued in patients co-infected with HIV and HBV, these patients should be closely monitored for evidence of exacerbation of hepatitis (see section 4.4).

Paediatric population

The safety and efficacy of the fixed-dose combination of efavirenz/emtricitabine/tenofovir disoproxil in children under the age of 18 years have not been established (see section 5.2).

Method of administration

Efavirenz/Emtricitabine/Tenofovir disoproxil tablets should be swallowed whole with water, once daily.

4.3. Contraindications

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

Severe hepatic impairment (CPT, Class C) (see section 5.2).

Co-administration with terfenadine, astemizole, cisapride, midazolam, triazolam, pimozide, bepridil, or ergot alkaloids (for example, ergotamine, dihydroergotamine, ergonovine, and methylergonovine). Competition for cytochrome P450 (CYP) 3A4 by efavirenz could result in inhibition of metabolism and create the potential for serious and/or life-threatening adverse reactions (for example, cardiac arrhythmias, prolonged sedation or respiratory depression) (see section 4.5).

Co-administration with elbasvir/grazoprevir due to the expected significant decreases in plasma concentrations of elbasvir and grazoprevir. This effect is due to induction of CYP3A4 or P-gp by efavirenz and may result in loss of therapeutic effect of elbasvir/grazoprevir (see section 4.5).

Co-administration with voriconazole. Efavirenz significantly decreases voriconazole plasma concentrations while voriconazole also significantly increases efavirenz plasma concentrations. Since Efavirenz/Emtricitabine/Tenofovir disoproxil is a fixed-dose combination product, the dose of efavirenz cannot be altered (see section 4.5).

Co-administration with herbal preparations containing St. John's wort (Hypericum perforatum) due to the risk of decreased plasma concentrations and reduced clinical effects of efavirenz (see section 4.5).

Administration to patients with:

- a family history of sudden death or of congenital prolongation of the QTc interval on electrocardiograms, or with any other clinical condition known to prolong the QTc interval.

- a history of symptomatic cardiac arrhythmias or with clinically relevant bradycardia or with congestive cardiac failure accompanied by reduced left ventricle ejection fraction.

- severe disturbances of electrolyte balance e.g. hypokalemia or hypomagnesemia.

Co-administration with medicinal products that are known to prolong the QTc interval (proarrhythmic). These medicinal products include:

- antiarrhythmics of classes IA and III,

- neuroleptics, antidepressive agents,

- certain antibiotics including some agents of the following classes: macrolides, fluoroquinolones, imidazole and triazole antifungal agents,

- certain non-sedating antihistamines (terfenadine, astemizole),

- cisapride,

- flecainide,

- certain antimalarials,

- methadone (see sections 4.4, 4.5 and 5.1).

4.4. Special warnings and precautions for use

Co-administration with other medicinal products

As a fixed combination, Efavirenz/Emtricitabine/Tenofovir disoproxil should not be administered concomitantly with other medicinal products containing the same active components, emtricitabine or tenofovir disoproxil.

This medicine should not be co-administered with products containing efavirenz unless needed for dose adjustment e.g. with rifampicin (see section 4.2). Due to similarities with emtricitabine, Efavirenz/Emtricitabine/Tenofovir disoproxil should not be administered concomitantly with other cytidine analogues, such as lamivudine (see section 4.5). This medicine should not be administered concomitantly with adefovir dipivoxil or with medicinal products containing tenofovir alafenamide.

Co-administration of Efavirenz/Emtricitabine/Tenofovir disoproxil and didanosine is not recommended (see section 4.5).

Co-administration of Efavirenz/Emtricitabine/Tenofovir disoproxil and sofosbuvir/velpatasvir or sofosbuvir/velpatasvir/voxilaprevir is not recommended since plasma concentrations of velpatasvir and voxilaprevir are expected to decrease following co-administration with efavirenz leading to reduced therapeutic effect of sofosbuvir/velpatasvir or sofosbuvir/velpatasvir/voxilaprevir (see section 4.5).

No data are available on the safety and efficacy Efavirenz/Emtricitabine/Tenofovir disoproxil in combination with other antiretroviral agents.

Concomitant use of Ginkgo biloba extracts is not recommended (see section 4.5).

Switching from a PI-based antiretroviral regimen

Currently available data indicate a trend that in patients on a PI-based antiretroviral regimen the switch to the fixed-dose combination of efavirenz/emtricitabine/tenofovir disoproxil may lead to a reduction of the response to the therapy (see section 5.1). These patients should be carefully monitored for rises in viral load and, since the safety profile of efavirenz differs from that of protease inhibitors, for adverse reactions.

Opportunistic infections

Patients receiving Efavirenz/Emtricitabine/Tenofovir disoproxil 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.

Transmission of HIV

While effective viral suppression with antiretroviral therapy has been proven to substantially reduce the risk of sexual transmission, a residual risk cannot be excluded. Precautions to prevent transmission should be taken in accordance with national guidelines.

Effect of food

The administration of Efavirenz/Emtricitabine/Tenofovir disoproxil with food may increase efavirenz exposure (see section 5.2) and may lead to an increase in frequency of adverse reactions (see section 4.8). It is recommended that Efavirenz/Emtricitabine/Tenofovir disoproxil be taken on an empty stomach, preferably at bedtime.

Liver disease

The pharmacokinetics, safety and efficacy of the fixed-dose combination of efavirenz/emtricitabine/tenofovir disoproxil have not been established in patients with significant underlying liver disorders (see section 5.2). Efavirenz/Emtricitabine/Tenofovir disoproxil is contraindicated in patients with severe hepatic impairment (see section 4.3) and not recommended in patients with moderate hepatic impairment. Since efavirenz is principally metabolised by the CYP system, caution should be exercised in administering Efavirenz/Emtricitabine/Tenofovir disoproxil to patients with mild hepatic impairment. These patients should be carefully monitored for efavirenz adverse reactions, especially nervous system symptoms. Laboratory tests should be performed to evaluate their liver disease at periodic intervals (see section 4.2).

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 or persistent elevations of serum transaminases to greater than 5 times the upper limit of the normal range, the benefit of continued therapy with Efavirenz/Emtricitabine/Tenofovir disoproxil needs to be weighed against the potential risks of significant liver toxicity. In such patients, interruption or discontinuation of treatment must be considered (see section 4.8).

In patients treated with other medicinal products associated with liver toxicity, monitoring of liver enzymes is also recommended.

Hepatic events

Post-marketing reports of hepatic failure also occurred in patients with no pre-existing hepatic disease or other identifiable risk factors (see section 4.8). Liver enzyme monitoring should be considered for all patients independent of pre-existing hepatic dysfunction or other risk factors.

Patients with HIV and hepatitis B (HBV) or C virus (HCV) co-infection

Patients with chronic hepatitis B or C and treated with CART are at an increased risk for severe and potentially fatal hepatic adverse reactions.

Physicians should refer to current HIV treatment guidelines for the optimal management of HIV infection in patients co-infected with HBV.

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.

The safety and efficacy of the fixed-dose combination of efavirenz/emtricitabine/tenofovir disoproxil have not been studied for the treatment of chronic HBV infection. Emtricitabine and tenofovir individually and in combination have shown activity against HBV in pharmacodynamic studies (see section 5.1). Limited clinical experience suggests that emtricitabine and tenofovir disoproxil have an anti-HBV activity when used in antiretroviral combination therapy to control HIV infection. Discontinuation of Efavirenz/Emtricitabine/Tenofovir disoproxil therapy in patients co-infected with HIV and HBV may be associated with severe acute exacerbations of hepatitis. Patients co-infected with HIV and HBV who discontinue this medicine must be closely monitored with both clinical and laboratory follow-up for at least four months after stopping treatment with Efavirenz/Emtricitabine/Tenofovir disoproxil. If appropriate, resumption of anti-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.

QTc Prolongation

QTc prolongation has been observed with the use of efavirenz (see sections 4.5 and 5.1). For patients at increased risk of Torsade de Pointes or who are receiving medicinal products with a known risk for Torsade de Pointes, consider alternatives to Efavirenz/Emtricitabine/Tenofovir disoproxil.

Psychiatric symptoms

Psychiatric adverse reactions have been reported in patients treated with efavirenz. Patients with a prior history of psychiatric disorders appear to be at greater risk of serious psychiatric adverse reactions. In particular, severe depression was more common in those with a history of depression. There have also been post-marketing reports of severe depression, death by suicide, delusions, psychosis-like behaviour and catatonia. Patients should be advised that if they experience symptoms such as severe depression, psychosis or suicidal ideation, they should contact their doctor immediately to assess the possibility that the symptoms may be related to the use of efavirenz, and if so, to determine whether the risk of continued therapy outweighs the benefits (see section 4.8).

Nervous system symptoms

Symptoms including, but not limited to, dizziness, insomnia, somnolence, impaired concentration and abnormal dreaming are frequently reported undesirable effects in patients receiving efavirenz 600 mg daily in clinical studies. Dizziness was also seen in clinical studies with emtricitabine and tenofovir disoproxil. Headache has been reported in clinical studies with emtricitabine (see section 4.8). Nervous system symptoms associated with efavirenz usually begin during the first one or two days of therapy and generally resolve after the first two to four weeks. Patients should be informed that if they do occur, these common symptoms are likely to improve with continued therapy and are not predictive of subsequent onset of any of the less frequent psychiatric symptoms.

Seizures

Convulsions have been observed in patients receiving efavirenz, generally in the presence of a known medical history of seizures. Patients who are receiving concomitant anticonvulsant medicinal products primarily metabolised by the liver, such as phenytoin, carbamazepine and phenobarbital, may require periodic monitoring of plasma levels. In an interaction study, carbamazepine plasma concentrations were decreased when carbamazepine was co-administered with efavirenz (see section 4.5). Caution must be taken in any patient with a history of seizures.

Renal impairment

Efavirenz/Emtricitabine/Tenofovir disoproxil is not recommended for patients with moderate or severe renal impairment (creatinine clearance < 50 ml/min). Patients with moderate or severe renal impairment require a dose adjustment of emtricitabine and tenofovir disoproxil that cannot be achieved with the combination tablet (see sections 4.2 and 5.2). Use of this medicine should be avoided with concurrent or recent use of a nephrotoxic medicinal product. If concomitant use of Efavirenz/Emtricitabine/Tenofovir disoproxil and nephrotoxic agents (e.g. aminoglycosides, amphotericin B, foscarnet, ganciclovir, pentamidine, vancomycin, cidofovir, interleukin-2) is unavoidable, renal function must be monitored weekly (see section 4.5).

Cases of acute renal failure after initiation of high dose or multiple non-steroidal anti-inflammatory drugs (NSAIDs) have been reported in patients treated with tenofovir disoproxil and with risk factors for renal dysfunction. If Efavirenz/Emtricitabine/Tenofovir disoproxil is co-administered with an NSAID, renal function should be monitored adequately.

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

It is recommended that creatinine clearance is calculated in all patients prior to initiating therapy with Efavirenz/Emtricitabine/Tenofovir disoproxil and renal function (creatinine clearance and serum phosphate) is also monitored after two to four weeks of treatment, after three months of treatment and every three to six months thereafter in patients without renal risk factors. In patients with a history of renal dysfunction or in patients who are at risk of renal dysfunction, a more frequent monitoring of renal function is required.

If serum phosphate is < 1.5 mg/dl (0.48 mmol/l) or creatinine clearance is decreased to < 50 ml/min in any patient receiving Efavirenz/Emtricitabine/Tenofovir disoproxil, renal function must be re-evaluated within one week, including measurements of blood glucose, blood potassium and urine glucose concentrations (see section 4.8, proximal tubulopathy). Since Efavirenz/Emtricitabine/Tenofovir disoproxil is a combination product and the dosing interval of the individual components cannot be altered, treatment with this medicine must be interrupted in patients with confirmed creatinine clearance < 50 ml/min or decreases in serum phosphate to < 1.0 mg/dl (0.32 mmol/l). Interrupting treatment with this medicine should also be considered in case of progressive decline of renal function when no other cause has been identified. Where discontinuation of therapy with one of the components of Efavirenz/Emtricitabine/Tenofovir disoproxil is indicated or where dose modification is necessary, separate preparations of efavirenz, emtricitabine and tenofovir disoproxil are available.

Bone effects

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

Tenofovir disoproxil may also cause a reduction in bone mineral density (BMD).

In a 144-week controlled clinical study that compared tenofovir disoproxil with stavudine in combination with lamivudine and efavirenz in antiretroviral-naïve patients, small decreases in BMD of the hip and spine were observed in both treatment groups. Decreases in bone mineral density of spine and changes in bone biomarkers from baseline were significantly greater in the tenofovir disoproxil treatment group at 144 weeks. Decreases in bone mineral density of the hip were significantly greater in this group until 96 weeks. However, there was no increased risk of fractures or evidence for clinically relevant bone abnormalities over 144 weeks in this study.

In other studies (prospective and cross-sectional), the most pronounced decreases in BMD were seen in patients treated with tenofovir disoproxil as part of a regimen containing a boosted protease inhibitor. Overall, in view of the bone abnormalities associated with tenofovir disoproxil and the limitations 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 that are at a high risk for fractures.

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

Skin reactions

Mild-to-moderate rash has been reported with the individual components of Efavirenz/Emtricitabine/Tenofovir disoproxil. The rash associated with the efavirenz component usually resolves with continued therapy. Appropriate antihistamines and/or corticosteroids may improve tolerability and hasten the resolution of rash.

Severe rash associated with blistering, moist desquamation or ulceration has been reported in less than 1% of patients treated with efavirenz (see section 4.8). The incidence of erythema multiforme or Stevens-Johnson syndrome was approximately 0.1%. Efavirenz/Emtricitabine/Tenofovir disoproxil must be discontinued in patients developing severe rash associated with blistering, desquamation, mucosal involvement or fever. Experience with efavirenz in patients who discontinued other antiretroviral agents of the NNRTI class is limited. This medicine is not recommended for patients who have had a life-threatening cutaneous reaction (e.g. Stevens-Johnson syndrome) while taking an NNRTI.

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.

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 are 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.

Patients with HIV-1 harbouring mutations

Efavirenz/Emtricitabine/Tenofovir disoproxil should be avoided in patients with HIV-1 harbouring the K65R, M184V/I or K103N mutation (see sections 4.1 and 5.1).

Elderly

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

Excipients

This medicine contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially 'sodium-free'.

4.5. Interaction with other medicinal products and other forms of interaction

As Efavirenz/Emtricitabine/Tenofovir disoproxil contains efavirenz, emtricitabine and tenofovir disoproxil, any interactions that have been identified with these agents individually may occur with this medicine. Interaction studies with these agents have only been performed in adults.

As a fixed combination, Efavirenz/Emtricitabine/Tenofovir disoproxil should not be administered concomitantly with other medicinal products containing the components, emtricitabine or tenofovir disoproxil. This medicine should not be co-administered with products containing efavirenz unless needed for dose adjustment e.g. with rifampicin (see section 4.2). Due to similarities with emtricitabine, this medicine should not be administered concomitantly with other cytidine analogues, such as lamivudine. Efavirenz/Emtricitabine/Tenofovir disoproxil should not be administered concomitantly with adefovir dipivoxil or with medicinal products containing tenofovir alafenamide.

Efavirenz is an in vivo inducer of CYP3A4, CYP2B6 and UGT1A1. Compounds that are substrates of these enzymes may have decreased plasma concentrations when co-administered with efavirenz. Efavirenz may be an inducer of CYP2C19 and CYP2C9; however, inhibition has also been observed in vitro and the net effect of co-administration with substrates of these enzymes is not clear (see section 5.2).

Co-administration of efavirenz with metamizole, which is an inducer of metabolising enzymes including CYP2B6 and CYP3A4 may cause a reduction in plasma concentrations of efavirenz with potential decrease in clinical efficacy. Therefore, caution is advised when metamizole and efavirenz are administered concurrently; clinical response and/or drug levels should be monitored as appropriate.

Efavirenz exposure may be increased when given with medicinal products (for example ritonavir) or food (for example, grapefruit juice) which inhibit CYP3A4 or CYP2B6 activity. Compounds or herbal preparations (for example Ginkgo biloba extracts and St. John's wort) which induce these enzymes may give rise to decreased plasma concentrations of efavirenz. Concomitant use of St. John's wort is contraindicated (see section 4.3). Concomitant use of Ginkgo biloba extracts is not recommended (see section 4.4).

In vitro and clinical pharmacokinetic interaction studies have shown the potential for CYP-mediated interactions involving emtricitabine and tenofovir disoproxil with other medicinal products is low.

Cannabinoid test interaction

Efavirenz does not bind to cannabinoid receptors. False-positive urine cannabinoid test results have been reported with some screening assays in uninfected and HIV infected subjects receiving efavirenz.

Confirmatory testing by a more specific method such as gas chromatography/mass spectrometry is recommended in such cases.

Contraindications of concomitant use

Efavirenz/Emtricitabine/Tenofovir disoproxil must not be administered concurrently with terfenadine, astemizole, cisapride, midazolam, triazolam, pimozide, bepridil, or ergot alkaloids (for example, ergotamine, dihydroergotamine, ergonovine, and methylergonovine), since inhibition of their metabolism may lead to serious, life-threatening events (see section 4.3).

Elbasvir/grazoprevir: Co-administration of <Product Name> with elbasvir/grazoprevir is contraindicated because it may lead to loss of virologic response to elbasvir/grazoprevir (see section 4.3 and Table 1).

Voriconazole: Co-administration of standard doses of efavirenz and voriconazole is contraindicated. Since Efavirenz/Emtricitabine/Tenofovir disoproxil is a fixed-dose combination product, the dose of efavirenz cannot be altered; therefore, voriconazole and this medicine must not be co-administered (see section 4.3 and Table 1).

St. John's wort (Hypericum perforatum): Co-administration of Efavirenz/Emtricitabine/Tenofovir disoproxil and St. John's wort or herbal preparations containing St. John's wort is contraindicated. Plasma levels of efavirenz can be reduced by concomitant use of St. John's wort due to induction of active substance metabolising enzymes and/or transport proteins by St. John's wort. If a patient is already taking St. John's wort, stop St. John's wort, check viral levels and if possible efavirenz levels. Efavirenz levels may increase on stopping St. John's wort. The inducing effect of St. John's wort may persist for at least 2 weeks after cessation of treatment (see section 4.3).

QT Prolonging medicinal products:

Efavirenz/Emtricitabine/Tenofovir disoproxil is contraindicated with concomitant use of medicinal products that are known to prolong the QTc interval and could lead to Torsade de Pointes, such as: antiarrhythmics of classes IA and III, neuroleptics and antidepressant agents, certain antibiotics including some agents of the following classes: macrolides, fluoroquinolones, imidazole, and triazole antifungal agents, certain non-sedating antihistaminics (terfenadine, astemizole), cisapride, flecainide, certain antimalarials and methadone (see section 4.3).

Concomitant use not recommended

Atazanavir / ritonavir: Insufficient data are available to make a dosing recommendation for atazanavir / ritonavir in combination with Efavirenz/Emtricitabine/Tenofovir disoproxil. Therefore co-administration of atazanavir / ritonavir and this medicine is not recommended (see Table 1).

Didanosine: Co-administration of Efavirenz/Emtricitabine/Tenofovir disoproxil and didanosine is not recommended (see Table 1).

Praziquantel: Concomitant use with efavirenz is not recommended due to significant decrease in plasma concentrations of praziquantel, with risk of treatment failure due to increased hepatic metabolism by efavirenz. In case the combination is needed, an increased dose of praziquantel could be considered.

Sofosbuvir/velpatasvir and sofosbuvir/velpatasvir/voxilaprevir: Co-administration of Efavirenz/Emtricitabine/Tenofovir disoproxil and sofosbuvir/velpatasvir or sofosbuvir/velpatasvir/voxilaprevir is not recommended (see section 4.4 and Table 1).

Renally eliminated medicinal products: Since emtricitabine and tenofovir are primarily eliminated by the kidneys, co-administration of Efavirenz/Emtricitabine/Tenofovir disoproxil with medicinal products that reduce renal function or compete for active tubular secretion (e.g. cidofovir) may increase serum concentrations of emtricitabine, tenofovir and/or the co-administered medicinal products.

Use of this medicine should be avoided with concurrent or recent use of a nephrotoxic medicinal product. Some examples include, but are not limited to, aminoglycosides, amphotericin B, foscarnet, ganciclovir, pentamidine, vancomycin, cidofovir or interleukin-2 (see section 4.4).

Other interactions

Interactions between Efavirenz/Emtricitabine/Tenofovir disoproxil or its individual component(s) and other medicinal products are listed in Table 1 below (increase is indicated as “↑”, decrease as “↓”, no change as “↔”, twice daily as “b.i.d.”, once daily as “q.d.” and once every 8 hours as “q8h”). If available, 90% confidence intervals are shown in parentheses.

Table 1: Interactions between Efavirenz/Emtricitabine/Tenofovir disoproxil or its individual components and other medicinal products

Medicinal product

by therapeutic areas

Effects on active substance levels

Mean percent change in AUC, Cmax, Cmin with 90% confidence intervals if available

(mechanism)

Recommendation concerning co-administration with Efavirenz/Emtricitabine/Tenofovir disoproxil

(efavirenz 600 mg, emtricitabine 200 mg, tenofovir disoproxil 245 mg)

ANTI-INFECTIVES

HIV antivirals

Protease inhibitors

Atazanavir/ritonavir/ Tenofovir disoproxil

(300 mg q.d./100 mg q.d./245 mg q.d.)

Atazanavir:

AUC: ↓ 25% (↓ 42 to ↓ 3)

Cmax: ↓ 28% (↓ 50 to ↑ 5)

Cmin: ↓ 26% (↓ 46 to ↑ 10)

Co-administration of atazanavir/ritonavir with tenofovir resulted in increased exposure to tenofovir. Higher tenofovir concentrations could potentiate tenofovir-associated adverse events, including renal disorders.

Co-administration of atazanavir/ritonavir and Efavirenz/Emtricitabine/Tenofovir disoproxil is not recommended.

Atazanavir/ritonavir/Efavirenz

(400 mg q.d./100 mg q.d./600 mg q.d., all administered with food)

Atazanavir (pm):

AUC: ↔* (↓ 9% to ↑ 10%)

Cmax: ↑ 17%* (↑ 8 to ↑ 27)

Cmin: ↓ 42%* (↓ 31 to ↓ 51)

Atazanavir/ritonavir/Efavirenz

(400 mg q.d./200 mg q.d./600 mg q.d., all administered with food)

Atazanavir (pm):

AUC: ↔*/** (↓ 10% to ↑ 26%)

Cmax: ↔*/** (↓ 5% to ↑ 26%)

Cmin: ↑ 12%*/** (↓ 16 to ↑ 49)

(CYP3A4 induction).

* When compared to atazanavir 300 mg/ritonavir 100 mg q.d. in the evening without efavirenz. This decrease in atazanavir Cmin might negatively impact the efficacy of atazanavir.

** based on historical comparison.

Co-administration of efavirenz with atazanavir/ritonavir is not recommended.

Atazanavir/ritonavir/Emtricitabine

Interaction not studied.

Darunavir/ritonavir/Efavirenz

(300 mg b.i.d.*/100 mg b.i.d./600 mg q.d.)

*lower than recommended doses; similar findings are expected with recommended doses.

Darunavir:

AUC: ↓ 13%

Cmin: ↓ 31%

Cmax: ↓ 15%

(CYP3A4 induction)

Efavirenz:

AUC: ↑ 21%

Cmin: ↑ 17%

Cmax: ↑ 15%

(CYP3A4 inhibition)

Efavirenz/Emtricitabine/Tenofovir disoproxil in combination with darunavir/ritonavir 800/100 mg once daily may result in suboptimal darunavir Cmin. If Efavirenz/Emtricitabine/Tenofovir disoproxil is to be used in combination with darunavir/ritonavir, the darunavir/ritonavir 600/100 mg twice daily regimen should be used.

Darunavir/ritonavir/Tenofovir disoproxil

(300 mg b.i.d.*/100 mg b.i.d./245mg q.d.)

*lower than recommended dose

Darunavir:

AUC: ↔

Cmin: ↔

Tenofovir:

AUC: ↑ 22%

Cmin: ↑ 37%

Darunavir/ritonavir should be used with caution in combination with Efavirenz/Emtricitabine/Tenofovir disoproxil. See ritonavir row below.

Monitoring of renal function may be indicated, particularly in patients with underlying systemic or renal disease, or in patients taking nephrotoxic agents.

Darunavir/ritonavir/Emtricitabine

Interaction not studied. Based on the different elimination pathways, no interaction is expected.

Fosamprenavir/ritonavir/Efavirenz

(700 mg b.i.d./100 mg b.i.d./600 mg q.d.)

No clinically significant pharmacokinetic interaction.

Efavirenz/Emtricitabine/Tenofovir disoproxil and fosamprenavir/ritonavir can be co-administered without dose adjustment.

See ritonavir row below.

Fosamprenavir/ritonavir/Emtricitabine

Interaction not studied.

Fosamprenavir/ritonavir/Tenofovir disoproxil

Interaction not studied.

Indinavir/Efavirenz

(800 mg q8h/200 mg q.d.)

Efavirenz:

AUC: ↔

Cmax: ↔

Cmin: ↔

Indinavir:

AUC: ↓ 31% (↓ 8 to ↓ 47)

Cmin: ↓ 40%

A similar reduction in indinavir exposures was observed when indinavir 1,000 mg q8h was given with efavirenz 600 mg q.d.

(CYP3A4 induction)

For co-administration of efavirenz with low-dose ritonavir in combination with a protease inhibitor, see section on ritonavir below.

Insufficient data are available to make a dosing recommendation for indinavir when dosed with Efavirenz/Emtricitabine/Tenofovir. While the clinical significance of decreased indinavir concentrations has not been established, the magnitude of the observed pharmacokinetic interaction should be taken into consideration when choosing a regimen containing both efavirenz, a component of Efavirenz/Emtricitabine/Tenofovir disoproxil, and indinavir.

Indinavir/Emtricitabine

(800 mg q8h/200 mg q.d.)

Indinavir:

AUC: ↔

Cmax: ↔

Emtricitabine:

AUC: ↔

Cmax: ↔

Indinavir/Tenofovir disoproxil

(800 mg q8h/245 mg q.d.)

Indinavir:

AUC: ↔

Cmax: ↔

Tenofovir:

AUC: ↔

Cmax: ↔

Lopinavir/ritonavir/Tenofovir disoproxil

(400 mg b.i.d./100 mg b.i.d./245 mg q.d.)

Lopinavir/Ritonavir:

AUC: ↔

Cmax: ↔

Cmin: ↔

Tenofovir:

AUC: ↑ 32% (↑ 25 to ↑ 38)

Cmax: ↔

Cmin: ↑ 51% (↑ 37 to ↑ 66)

Higher tenofovir concentrations could potentiate tenofovir-associated adverse events, including renal disorders.

Insufficient data are available to make a dosing recommendation for lopinavir/ritonavir when dosed with the fixed-dose combination of efavirenz/emtricitabine/tenofovir disoproxil. Co-administration of lopinavir/ritonavir and Efavirenz/Emtricitabine/Tenofovir disoproxil is not recommended.

Lopinavir/ritonavir soft capsules or oral solution/Efavirenz

Lopinavir/ritonavir tablets/Efavirenz

(400/100 mg b.i.d./600 mg q.d.)

(500/125 mg b.i.d./600 mg q.d.)

Substantial decrease in lopinavir exposure, necessitating dosage adjustment of lopinavir/ritonavir. When used in combination with efavirenz and two NRTIs, 533/133 mg lopinavir/ritonavir (soft capsules) twice daily yielded similar lopinavir plasma concentrations as compared to lopinavir/ritonavir (soft capsules) 400/100 mg twice daily without efavirenz (historical data).

Lopinavir concentrations: ↓ 30-40%

Lopinavir concentrations: similar to lopinavir/ritonavir 400/100 mg twice daily without efavirenz. Dosage adjustment of lopinavir/ritonavir is necessary when given with efavirenz. For co-administration of efavirenz with low-dose ritonavir in combination with a protease inhibitor, see section on ritonavir below.

Lopinavir/ritonavir/Emtricitabine

Interaction not studied.

Ritonavir/Efavirenz

(500 mg b.i.d./600 mg q.d.)

Ritonavir:

Morning AUC: ↑ 18% (↑ 6 to ↑ 33)

Evening AUC: ↔

Morning Cmax: ↑ 24% (↑ 12 to ↑ 38)

Evening Cmax: ↔

Morning Cmin: ↑ 42% (↑ 9 to ↑ 86)

Evening Cmin: ↑ 24% (↑ 3 to ↑ 50)

Efavirenz:

AUC: ↑ 21% (↑ 10 to ↑ 34)

Cmax: ↑ 14% (↑ 4 to ↑ 26)

Cmin: ↑ 25% (↑ 7 to ↑ 46)

(inhibition of CYP-mediated oxidative metabolism)

When efavirenz was given with ritonavir 500 mg or 600 mg twice daily, the combination was not well tolerated (for example, dizziness, nausea, paraesthesia and elevated liver enzymes occurred). Sufficient data on the tolerability of efavirenz with low-dose ritonavir (100 mg, once or twice daily) are not available.

Co-administration of ritonavir at doses of 600 mg and Efavirenz/Emtricitabine/Tenofovir disoproxilis not recommended. When using Efavirenz/Emtricitabine/Tenofovir disoproxil with low-dose ritonavir, the possibility of an increase in the incidence of efavirenz-associated adverse events should be considered, due to possible pharmacodynamic interaction.

Ritonavir/Emtricitabine

Interaction not studied.

Ritonavir/Tenofovir disoproxil

Interaction not studied.

Saquinavir/ritonavir/Efavirenz

Interaction not studied. For co-administration of efavirenz with low-dose ritonavir in combination with a protease inhibitor, see section on ritonavir above.

Insufficient data are available to make a dosing recommendation for saquinavir/ritonavir when dosed with Efavirenz/Emtricitabine/Tenofovir disoproxil.

Co-administration of saquinavir/ritonavir and Efavirenz/Emtricitabine/Tenofovir disoproxil is not recommended. Use of Efavirenz/Emtricitabine/Tenofovir disoproxil in combination with saquinavir as the sole protease inhibitor is not recommended.

Saquinavir/ritonavir/Tenofovir disoproxil

There were no clinically significant pharmacokinetic interactions when tenofovir disoproxil was co-administered with ritonavir boosted saquinavir.

Saquinavir/ritonavir/Emtricitabine

Interaction not studied.

CCR5 antagonist

Maraviroc/Efavirenz

(100 mg b.i.d./600 mg q.d.)

Maraviroc:

AUC12h: ↓ 45% (↓ 38 to ↓ 51)

Cmax: ↓ 51% (↓ 37 to ↓ 62)

Efavirenz concentrations not measured, no effect is expected.

Refer to the Summary of Product Characteristics for the medicinal product containing maraviroc.

Maraviroc/Tenofovir disoproxil

(300 mg b.i.d./245 mg q.d.)

Maraviroc:

AUC12h: ↔

Cmax: ↔

Tenofovir concentrations not measured, no effect is expected.

Maraviroc/Emtricitabine

Interaction not studied.

Integrase strand transfer inhibitor

Raltegravir/Efavirenz

(400 mg single dose/-)

Raltegravir:

AUC: ↓ 36%

C12h: ↓ 21%

Cmax: ↓ 36%

(UGT1A1 induction)

Efavirenz/Emtricitabine/Tenofovir disoproxil and raltegravir can be co-administered without dose adjustment.

Raltegravir/Tenofovir disoproxil

(400 mg b.i.d./-)

Raltegravir:

AUC: ↑ 49%

C12h: ↑ 3%

Cmax: ↑ 64%

(mechanism of interaction unknown)

Tenofovir:

AUC: ↓ 10%

C12h: ↓ 13%

Cmax: ↓ 23%

Raltegravir/Emtricitabine

Interaction not studied.

NRTIs and NNRTIs

NRTIs/Efavirenz

Specific interaction studies have not been performed with efavirenz and NRTIs other than lamivudine, zidovudine and tenofovir disoproxil. Clinically significant interactions have not been found and would not be expected since the NRTIs are metabolised via a different route than efavirenz and would be unlikely to compete for the same metabolic enzymes and elimination pathways.

Due to the similarity between lamivudine and emtricitabine, a component of Efavirenz/Emtricitabine/Tenofovir disoproxil, Efavirenz/Emtricitabine/Tenofovir disoproxil should not be administered concomitantly with lamivudine (see section 4.4).

NNRTIs/Efavirenz

Interaction not studied.

Since use of two NNRTIs proved not beneficial in terms of efficacy and safety, co-administration of Efavirenz/Emtricitabine/Tenofovir disoproxil and another NNRTI is not recommended.

Didanosine/Tenofovir disoproxil

Co-administration of tenofovir disoproxil and didanosine results in a 40-60% increase in systemic exposure to didanosine.

Co-administration of Efavirenz/Emtricitabine/Tenofovir disoproxil and didanosine is not recommended.

Increased systemic exposure to didanosine may increase didanosine related adverse reactions. Rarely, pancreatitis and lactic acidosis, sometimes fatal, have been reported. Co-administration of tenofovir disoproxil and didanosine at a dose of 400 mg daily has been associated with a significant decrease in CD4 cell count, possibly due to an intracellular interaction increasing phosphorylated (i.e. active) didanosine. A decreased dosage of 250 mg didanosine co-administered with tenofovir disoproxil therapy has been associated with reports of high rates of virological failure within several tested combinations for the treatment of HIV-1 infection.

Didanosine/Efavirenz

Interaction not studied.

Didanosine/Emtricitabine

Interaction not studied.

Hepatitis C antivirals

Elbasvir/Grazoprevir + Efavirenz

Elbasvir:

AUC: ↓ 54%

Cmax: ↓ 45%

CYP3A4 or P-gp induction - effect on elbasvir)

Grazoprevir:

AUC: ↓ 83%

Cmax: ↓ 87%

CYP3A4 or P-gp induction - effect on grazoprevir)

Efavirenz:

AUC: ↔

Cmax: ↔

Co-administration of Efavirenz/Emtricitabine/Tenofovir disoproxil with elbasvir/grazoprevir is contraindicated because it may lead to loss of virologic response to elbasvir/grazoprevir. This loss is due to significant decreases in elbasvir/grazoprevir plasma concentrations caused by CYP3A4 or P-gp induction. Refer to the Summary of Product Characteristics for elbasvir/grazoprevir for more information.

Glecaprevir/Pibrentasvir/Efavirenz

Expected:

Glecaprevir: ↓

Pibrentasvir: ↓

Concomitant administration of glecaprevir/pibrentasvir with efavirenz, a component of Efavirenz/Emtricitabine/Tenofovir disoproxil may significantly decrease plasma concentrations of glecaprevir and pibrentasvir, leading to reduced therapeutic effect. Co-administration of glecaprevir/pibrentasvir with <Product Name>, is not recommended. Refer to the prescribing information for glecaprevir/pibrentasvir for more information.

Ledipasvir/Sofosbuvir

(90 mg/400 mg q.d.) +

Efavirenz/Emtricitabine/Tenofovir disoproxil

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

Ledipasvir:

AUC: ↓ 34% (↓ 41 to ↓ 25)

Cmax: ↓ 34% (↓ 41 to ↑ 25)

Cmin: ↓ 34% (↓ 43 to ↑ 24)

Sofosbuvir:

AUC: ↔

Cmax: ↔

GS-3310071:

AUC: ↔

Cmax: ↔

Cmin: ↔

Efavirenz:

AUC: ↔

Cmax: ↔

Cmin: ↔

Emtricitabine:

AUC: ↔

Cmax: ↔

Cmin: ↔

Tenofovir:

AUC: ↑ 98% (↑ 77 to ↑ 123)

Cmax: ↑ 79% (↑ 56 to ↑ 104)

Cmin: ↑ 163% (↑ 137 to ↑ 197)

No dose adjustment is recommended. The increased exposure of tenofovir could potentiate adverse reactions associated with tenofovir disoproxil, including renal disorders. Renal function should be closely monitored (see section 4.4).

Sofosbuvir/Velpatasvir

(400 mg q.d./ 100 mg q.d.) +

Efavirenz/Emtricitabine/Tenofovir disoproxil

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

Sofosbuvir:

AUC: ↔

Cmax: 38% (↑ 14 to ↑ 67)

GS-3310071:

AUC: ↔

Cmin: ↔

Velpatasvir:

AUC: ↓ 53% (↓ 61 to ↓ 43)

Cmax: ↓ 47% (↓ 57 to ↓ 36)

Cmin: ↓ 57% (↓ 64 to ↓ 48)

Efavirenz:

AUC: ↔

Cmax: ↔

Cmin: ↔

Emtricitabine:

AUC: ↔

Cmax: ↔

Cmin: ↔

Tenofovir:

AUC: ↑ 81% (↑ 68 to ↑ 94)

Cmax: ↑ 77% (↑ 53 to ↑ 104)

Cmin: ↑ 121% (↑ 100 to ↑ 143)

Concomitant administration of Efavirenz/Emtricitabine/Tenofovir disoproxil and sofosbuvir/velpatasvir or or sofosbuvir/velpatasvir/ voxilaprevir is expected to decrease plasma concentrations of velpatasvir.

Co-administration of Efavirenz/Emtricitabine/Tenofovir disoproxil with sofosbuvir/velpatasvir or sofosbuvir/velpatasvir/ voxilaprevir is not recommended (see section 4.4).

Sofosbuvir/Velpatasvir/Voxilaprevir (400 mg/100 mg/100 mg q.d.) +

Efavirenz/Emtricitabine/Tenofovir disoproxil

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

Interaction only studied with sofosbuvir/velpatasvir.

Expected:

Voxilaprevir: ↓

Sofosbuvir

(400 mg q.d.) +

Efavirenz/Emtricitabine/Tenofovir disoproxil

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

Sofosbuvir:

AUC: ↔

Cmax: ↓ 19% (↓ 40 to ↑ 10)

GS-3310071:

AUC: ↔

Cmax: ↓ 23% (↓ 30 to ↑ 16)

Efavirenz:

AUC: ↔

Cmax: ↔

Cmin: ↔

Emtricitabine:

AUC: ↔

Cmax: ↔

Cmin: ↔

Tenofovir:

AUC: ↔

Cmax: ↑ 25% (↑ 8 to ↑ 45)

Cmin: ↔

Efavirenz/Emtricitabine/Tenofovir disoproxiland sofosbuvir can be co-administered without dose adjustment.

Antibiotics

Clarithromycin/Efavirenz

(500 mg b.i.d./400 mg q.d.)

Clarithromycin:

AUC: ↓ 39% (↓ 30 to ↓ 46)

Cmax: ↓ 26% (↓ 15 to ↓ 35)

Clarithromycin 14-hydroxymetabolite:

AUC: ↑ 34% (↑ 18 to ↑ 53)

Cmax: ↑ 49% (↑ 32 to ↑ 69)

Efavirenz:

AUC: ↔

Cmax: ↑ 11% (↑ 3 to ↑ 19)

(CYP3A4 induction)

Rash developed in 46% of uninfected volunteers receiving efavirenz and clarithromycin.

The clinical significance of these changes in clarithromycin plasma levels is not known.

Alternatives to clarithromycin (e.g. azithromycin) may be considered. Other macrolide antibiotics, such as erythromycin, have not been studied in combination with the fixed-dose combination of efavirenz/emtricitabine/tenofovir disoproxil.

Clarithromycin/Emtricitabine

Interaction not studied.

Clarithromycin/Tenofovir disoproxil

Interaction not studied.

Antimycobacterials

Rifabutin/Efavirenz

(300 mg q.d./600 mg q.d.)

Rifabutin:

AUC: ↓ 38% (↓ 28 to ↓ 47)

Cmax: ↓ 32% (↓ 15 to ↓ 46)

Cmin: ↓ 45% (↓ 31 to ↓ 56)

Efavirenz:

AUC: ↔

Cmax: ↔

Cmin: ↓ 12% (↓ 24 to ↑ 1)

(CYP3A4 induction)

The daily dose of rifabutin should be increased by 50% when given with Efavirenz/Emtricitabine/Tenofovir disoproxil. Consider doubling the rifabutin dose in regimens where rifabutin is given 2 or 3 times a week in combination with Efavirenz/Emtricitabine/Tenofovir disoproxil. The clinical effect of this dose adjustment has not been adequately evaluated. Individual tolerability and virological response should be considered when making the dose adjustment (see section 5.2).

Rifabutin/Emtricitabine

Interaction not studied.

Rifabutin/Tenofovir disoproxil

Interaction not studied.

Rifampicin/Efavirenz

(600 mg q.d./600 mg q.d.)

Efavirenz:

AUC: ↓ 26% (↓ 15 to ↓ 36)

Cmax: ↓ 20% (↓ 11 to ↓ 28)

Cmin: ↓ 32% (↓ 15 to ↓ 46)

(CYP3A4 and CYP2B6 induction)

When Efavirenz/Emtricitabine/Tenofovir disoproxil is taken with rifampicin in patients weighing 50 kg or greater, an additional 200 mg/day (800 mg total) of efavirenz may provide exposure similar to a daily efavirenz dose of 600 mg when taken without rifampicin. The clinical effect of this dose adjustment has not been adequately evaluated. Individual tolerability and virological response should be considered when making the dose adjustment (see section 5.2). No dose adjustment of rifampicin is recommended when given with Efavirenz/Emtricitabine/Tenofovir disoproxil.

Rifampicin/Tenofovir disoproxil

(600 mg q.d./245 mg q.d.)

Rifampicin:

AUC: ↔

Cmax: ↔

Tenofovir:

AUC: ↔

Cmax: ↔

Rifampicin/Emtricitabine

Interaction not studied.

Antifungals

Itraconazole/Efavirenz

(200 mg b.i.d./600 mg q.d.)

Itraconazole:

AUC: ↓ 39% (↓ 21 to ↓ 53)

Cmax: ↓ 37% (↓ 20 to ↓ 51)

Cmin: ↓ 44% (↓ 27 to ↓ 58)

(decrease in itraconazole concentrations: CYP3A4 induction)

Hydroxyitraconazole:

AUC: ↓ 37% (↓ 14 to ↓ 55)

Cmax: ↓ 35% (↓ 12 to ↓ 52)

Cmin: ↓ 43% (↓ 18 to ↓ 60)

Efavirenz:

AUC: ↔

Cmax: ↔

Cmin: ↔

Since no dose recommendation can be made for itraconazole when used with Efavirenz/Emtricitabine/Tenofovir disoproxil, an alternative antifungal treatment should be considered.

Itraconazole/Emtricitabine

Interaction not studied.

Itraconazole/Tenofovir disoproxil

Interaction not studied.

Posaconazole/Efavirenz

(-/400 mg q.d.)

Posaconazole:

AUC: ↓ 50%

Cmax: ↓ 45%

(UDP-G induction)

Concomitant use of posaconazole and Efavirenz/Emtricitabine/Tenofovir disoproxil should be avoided unless the benefit to the patient outweighs the risk.

Posaconazole/Emtricitabine

Interaction not studied.

Posaconazole/Tenofovir disoproxil

Interaction not studied.

Voriconazole/Efavirenz

(200 mg b.i.d./400 mg q.d.)

Voriconazole:

AUC: ↓ 77%

Cmax: ↓ 61%

Efavirenz:

AUC: ↑ 44%

Cmax: ↑ 38%

(competitive inhibition of oxidative metabolism)

Co-administration of standard doses of efavirenz and voriconazole is contraindicated (see section 4.3).

Since Efavirenz/Emtricitabine/Tenofovir disoproxil is a fixed-dose combination product, the dose of efavirenz cannot be altered; therefore, voriconazole and Efavirenz/Emtricitabine/Tenofovir disoproxil must not be co-administered.

Voriconazole/Emtricitabine

Interaction not studied.

Voriconazole/Tenofovir disoproxil

Interaction not studied.

Antimalarials

Artemether/Lumefantrine/Efavirenz

(20/120 mg tablet, 6 doses of 4 tablets each over 3 days/600 mg q.d.)

Artemether:

AUC: ↓ 51%

Cmax: ↓ 21%

Dihydroartemisinin (active metabolite):

AUC: ↓ 46%

Cmax: ↓ 38%

Lumefantrine:

AUC: ↓ 21%

Cmax: ↔

Efavirenz:

AUC: ↓ 17%

Cmax: ↔

(CYP3A4 induction)

Since decreased concentrations of artemether, dihydroartemisinin, or lumefantrine may result in a decrease of antimalarial efficacy, caution is recommended when Efavirenz/Emtricitabine/Tenofovir disoproxil and artemether/lumefantrine tablets are co-administered.

Artemether/Lumefantrine/Emtricitabine

Interaction not studied.

Artemether/Lumefantrine/Tenofovir disoproxil

Interaction not studied.

Atovaquone and proguanil hydrochloride/Efavirenz

(250/100 mg single dose/600 mg q.d.)

Atovaquone:

AUC: ↓ 75% (↓ 62 to ↓ 84)

Cmax: ↓ 44% (↓ 20 to ↓ 61)

Proguanil:

AUC: ↓ 43% (↓ 7 to ↓ 65)

Cmax: ↔

Concomitant administration of atovaquone/proguanil with Efavirenz/Emtricitabine/Tenofovir disoproxil should be avoided.

Atovaquone and proguanil hydrochloride/Emtricitabine

Interaction not studied.

Atovaquone and proguanil hydrochloride/Tenofovir disoproxil

Interaction not studied.

ANTICONVULSANTS

Carbamazepine/Efavirenz

(400 mg q.d./600 mg q.d.)

Carbamazepine:

AUC: ↓ 27% (↓ 20 to ↓ 33)

Cmax: ↓ 20% (↓ 15 to ↓ 24)

Cmin: ↓ 35% (↓ 24 to ↓ 44)

Efavirenz:

AUC: ↓ 36% (↓ 32 to ↓ 40)

Cmax: ↓ 21% (↓ 15 to ↓ 26)

Cmin: ↓ 47% (↓ 41 to ↓ 53)

(decrease in carbamazepine concentrations: CYP3A4 induction; decrease in efavirenz concentrations: CYP3A4 and CYP2B6 induction)

Co-administration of higher doses of either efavirenz or carbamazepine has not been studied

No dose recommendation can be made for the use of Efavirenz/Emtricitabine/Tenofovir disoproxil with carbamazepine. An alternative anticonvulsant should be considered. Carbamazepine plasma levels should be monitored periodically.

Carbamazepine/Emtricitabine

Interaction not studied.

Carbamazepine/Tenofovir disoproxil

Interaction not studied.

Phenytoin, Phenobarbital, and other anticonvulsants that are substrates of CYP isozymes

Interaction not studied with efavirenz, emtricitabine, or tenofovir disoproxil. There is a potential for reduction or increase in the plasma concentrations of phenytoin, phenobarbital and other anticonvulsants that are substrates of CYP isozymes with efavirenz.

When Efavirenz/Emtricitabine/Tenofovir disoproxil is co-administered with an anticonvulsant that is a substrate of CYP isozymes, periodic monitoring of anticonvulsant levels should be conducted.

Valproic acid/Efavirenz

(250 mg b.i.d./600 mg q.d.)

No clinically significant effect on efavirenz pharmacokinetics. Limited data suggest there is no clinically significant effect on valproic acid pharmacokinetics.

Efavirenz/Emtricitabine/Tenofovir disoproxil and valproic acid can be co-administered without dose adjustment. Patients should be monitored for seizure control.

Valproic acid/Emtricitabine

Interaction not studied.

Valproic acid/Tenofovir disoproxil

Interaction not studied.

Vigabatrin/Efavirenz

Gabapentin/Efavirenz

Interaction not studied. Clinically significant interactions are not expected since vigabatrin and gabapentin are exclusively eliminated unchanged in the urine and are unlikely to compete for the same metabolic enzymes and elimination pathways as efavirenz.

Efavirenz/Emtricitabine/Tenofovir disoproxil and vigabatrin or gabapentin can be co-administered without dose adjustment.

Vigabatrin/Emtricitabine

Gabapentin/Emtricitabine

Interaction not studied.

Vigabatrin/Tenofovir disoproxil

Gabapentin/Tenofovir disoproxil

Interaction not studied.

ANTICOAGULANTS

Warfarin/Efavirenz

Acenocoumarol/Efavirenz

Interaction not studied. Plasma concentrations and effects of warfarin or acenocoumarol are potentially increased or decreased by efavirenz.

Dose adjustment of warfarin or acenocoumarol may be required when co-administered with Efavirenz/Emtricitabine/Tenofovir disoproxil.

ANTIDEPRESSANTS

Selective Serotonin Reuptake Inhibitors (SSRIs)

Sertraline/Efavirenz

(50 mg q.d./600 mg q.d.)

Sertraline:

AUC: ↓ 39% (↓ 27 to ↓ 50)

Cmax: ↓ 29% (↓ 15 to ↓ 40)

Cmin: ↓ 46% (↓ 31 to ↓ 58)

Efavirenz:

AUC: ↔

Cmax: ↑ 11% (↑ 6 to ↑ 16)

Cmin: ↔

(CYP3A4 induction)

When co-administered with Efavirenz/Emtricitabine/Tenofovir disoproxil, sertraline dose increases should be guided by clinical response.

Sertraline/Emtricitabine

Interaction not studied.

Sertraline/Tenofovir disoproxil

Interaction not studied.

Paroxetine/Efavirenz

(20 mg q.d./600 mg q.d.)

Paroxetine:

AUC: ↔

Cmax: ↔

Cmin: ↔

Efavirenz:

AUC: ↔

Cmax: ↔

Cmin: ↔

Efavirenz/Emtricitabine/Tenofovir disoproxil and paroxetine can be co-administered without dose adjustment.

Paroxetine/Emtricitabine

Interaction not studied.

Paroxetine/Tenofovir disoproxil

Interaction not studied.

Fluoxetine/Efavirenz

Interaction not studied. Since fluoxetine shares a similar metabolic profile with paroxetine, i.e. a strong CYP2D6 inhibitory effect, a similar lack of interaction would be expected for fluoxetine.

Efavirenz/Emtricitabine/Tenofovir disoproxil and fluoxetine can be co-administered without dose adjustment.

Fluoxetine/Emtricitabine

Interaction not studied.

Fluoxetine/Tenofovir disoproxil

Interaction not studied.

Norepinephrine and dopamine reuptake inhibitor

Bupropion/Efavirenz

[150 mg single dose (sustained release)/600 mg q.d.]

Bupropion:

AUC: ↓ 55% (↓ 48 to ↓ 62)

Cmax: ↓ 34% (↓ 21 to ↓ 47)

Hydroxybupropion:

AUC: ↔

Cmax: ↑ 50% (↑ 20 to ↑ 80)

(CYP2B6 induction)

Increases in bupropion dosage should be guided by clinical response, but the maximum recommended dose of bupropion should not be exceeded. No dose adjustment is necessary for efavirenz.

Bupropion/Emtricitabine

Interaction not studied.

Bupropion/Tenofovir disoproxil

Interaction not studied.

CARDIOVASCULAR AGENTS

Calcium Channel Blockers

Diltiazem/Efavirenz

(240 mg q.d./600 mg q.d.)

Diltiazem:

AUC: ↓ 69% (↓ 55 to ↓ 79)

Cmax: ↓ 60% (↓ 50 to ↓ 68)

Cmin: ↓ 63% (↓ 44 to ↓ 75)

Desacetyl diltiazem:

AUC: ↓ 75% (↓ 59 to ↓ 84)

Cmax: ↓ 64% (↓ 57 to ↓ 69)

Cmin: ↓ 62% (↓ 44 to ↓ 75)

N-monodesmethyl diltiazem:

AUC: ↓ 37% (↓ 17 to ↓ 52)

Cmax: ↓ 28% (↓ 7 to ↓ 44)

Cmin: ↓ 37% (↓ 17 to ↓ 52)

Efavirenz:

AUC: ↑ 11% (↑ 5 to ↑ 18)

Cmax: ↑ 16% (↑ 6 to ↑ 26)

Cmin: ↑ 13% (↑ 1 to ↑ 26)

(CYP3A4 induction)

The increase in efavirenz pharmacokinetic parameters is not considered clinically significant.

Dose adjustments of diltiazem when co-administered with Efavirenz/Emtricitabine/Tenofovir disoproxil should be guided by clinical response (refer to the Summary of Product Characteristics for diltiazem).

Diltiazem/Emtricitabine

Interaction not studied.

Diltiazem/Tenofovir disoproxil

Interaction not studied.

Verapamil, Felodipine, Nifedipine and Nicardipine

Interaction not studied with efavirenz, emtricitabine, or tenofovir disoproxil. When efavirenz is co-administered with a calcium channel blocker that is a substrate of the CYP3A4 enzyme, there is a potential for reduction in the plasma concentrations of the calcium channel blocker.

Dose adjustments of calcium channel blockers when co-administered with Efavirenz/Emtricitabine/Tenofovir disoproxil should be guided by clinical response (refer to the Summary of Product Characteristics for the calcium channel blocker).

LIPID LOWERING MEDICINAL PRODUCTS

HMG Co-A Reductase Inhibitors

Atorvastatin/Efavirenz

(10 mg q.d./600 mg q.d.)

Atorvastatin:

AUC: ↓ 43% (↓ 34 to ↓ 50)

Cmax: ↓ 12% (↓ 1 to ↓ 26)

2-hydroxy atorvastatin:

AUC: ↓ 35% (↓ 13 to ↓ 40)

Cmax: ↓ 13% (↓ 0 to ↓ 23)

4-hydroxy atorvastatin:

AUC: ↓ 4% (↓ 0 to ↓ 31)

Cmax: ↓ 47% (↓ 9 to ↓ 51)

Total active HMG Co-A reductase inhibitors:

AUC: ↓ 34% (↓ 21 to ↓ 41)

Cmax: ↓ 20% (↓ 2 to ↓ 26)

Cholesterol levels should be periodically monitored. Dosage adjustments of atorvastatin may be required when co-administered with Efavirenz/Emtricitabine/Tenofovir disoproxil (refer to the Summary of Product Characteristics for atorvastatin).

Atorvastatin/Emtricitabine

Interaction not studied.

Atorvastatin/Tenofovir disoproxil

Interaction not studied.

Pravastatin/Efavirenz

(40 mg q.d./600 mg q.d.)

Pravastatin:

AUC: ↓ 40% (↓ 26 to ↓ 57)

Cmax: ↓ 18% (↓ 59 to ↑ 12)

Cholesterol levels should be periodically monitored. Dosage adjustments of pravastatin may be required when co-administered with Efavirenz/Emtricitabine/Tenofovir disoproxil (refer to the Summary of Product Characteristics for pravastatin).

Pravastatin/Emtricitabine

Interaction not studied.

Pravastatin/Tenofovir disoproxil

Interaction not studied.

Simvastatin/Efavirenz

(40 mg q.d./600 mg q.d.)

Simvastatin:

AUC: ↓ 69% (↓ 62 to ↓ 73)

Cmax: ↓ 76% (↓ 63 to ↓ 79)

Simvastatin acid:

AUC: ↓ 58% (↓ 39 to ↓ 68)

Cmax: ↓ 51% (↓ 32 to ↓ 58)

Total active HMG Co-A reductase inhibitors:

AUC: ↓ 60% (↓ 52 to ↓ 68)

Cmax: ↓ 62% (↓ 55 to ↓ 78)

(CYP3A4 induction)

Co-administration of efavirenz with atorvastatin, pravastatin, or simvastatin did not affect efavirenz AUC or Cmax values.

Cholesterol levels should be periodically monitored. Dosage adjustments of simvastatin may be required when co-administered with Efavirenz/Emtricitabine/Tenofovir disoproxil (refer to the Summary of Product Characteristics for simvastatin).

Simvastatin/Emtricitabine

Interaction not studied.

Simvastatin/Tenofovir disoproxil

Interaction not studied.

Rosuvastatin/Efavirenz

Interaction not studied. Rosuvastatin is largely excreted unchanged via the faeces, therefore interaction with efavirenz is not expected

Efavirenz/Emtricitabine/Tenofovir disoproxil and rosuvastatin can be co-administered without dose adjustment.

Rosuvastatin/Emtricitabine

Interaction not studied.

Rosuvastatin/Tenofovir disoproxil

Interaction not studied.

HORMONAL CONTRACEPTIVES

Oral:

Ethinyloestradiol+Norgestimate/Efavirenz

(0.035 mg+0.25 mg q.d./600 mg q.d.)

Ethinyloestradiol:

AUC: ↔

Cmax: ↔

Cmin: ↓ 8% (↑ 14 to ↓ 25)

Norelgestromin (active metabolite):

AUC: ↓ 64% (↓ 62 to ↓ 67)

Cmax: ↓ 46% (↓ 39 to ↓ 52)

Cmin: ↓ 82% (↓ 79 to ↓ 85)

Levonorgestrel (active metabolite):

AUC: ↓ 83% (↓ 79 to ↓ 87)

Cmax: ↓ 80% (↓ 77 to ↓ 83)

Cmin: ↓ 86% (↓ 80 to ↓ 90)

(induction of metabolism)

Efavirenz: no clinically significant interaction.

The clinical significance of these effects is not known.

A reliable method of barrier contraception must be used in addition to hormonal contraceptives (see section 4.6).

Ethinyloestradiol/Tenofovir disoproxil

(-/245mg q.d.)

Ethinyloestradiol:

AUC: ↔

Cmax: ↔

Tenofovir:

AUC: ↔

Cmax: ↔

Norgestimate/Ethinyloestradiol/

Emtricitabine

Interaction not studied.

Injection:

Depomedroxyprogesterone acetate (DMPA)/Efavirenz

(150 mg IM single dose DMPA)

In a 3-month interaction study, no significant differences in MPA pharmacokinetic parameters were found between subjects receiving efavirenz-containing antiretroviral therapy and subjects receiving no antiretroviral therapy. Similar results were found by other investigators, although the MPA plasma levels were more variable in the second study. In both studies, plasma progesterone levels for subjects receiving efavirenz and DMPA remained low consistent with suppression of ovulation.

Because of the limited information available, a reliable method of barrier contraception must be used in addition to hormonal contraceptives (see section 4.6).

DMPA/Tenofovir disoproxil

Interaction not studied.

DMPA/Emtricitabine

Interaction not studied.

Implant:

Etonogestrel/Efavirenz

Decreased exposure of etonogestrel may be expected (CYP3A4 induction). There have been occasional post-marketing reports of contraceptive failure with etonogestrel in efavirenz-exposed patients.

A reliable method of barrier contraception must be used in addition to hormonal contraceptives (see section 4.6).

Etonogestrel/Tenofovir disoproxil

Interaction not studied.

Etonogestrel/Emtricitabine

Interaction not studied.

IMMUNOSUPPRESSANTS

Immunosuppressants metabolised by CYP3A4 (e.g. cyclosporine, tacrolimus, sirolimus)/Efavirenz

Interaction not studied.

↓ exposure of the immunosuppressant may be expected (CYP3A4 induction).

These immunosuppressants are not anticipated to impact exposure of efavirenz.

Dose adjustments of the immunosuppressant may be required. Close monitoring of immunosuppressant concentrations for at least two weeks (until stable concentrations are reached) is recommended when starting or stopping treatment with Efavirenz/Emtricitabine/Tenofovir disoproxil.

Tacrolimus/Emtricitabine/Tenofovir disoproxil

(0.1 mg/kg q.d./200 mg/245 mg q.d.)

Tacrolimus:

AUC: ↔

Cmax: ↔

C24h: ↔

Emtricitabine:

AUC: ↔

Cmax: ↔

C24h: ↔

Tenofovir disoproxil:

AUC: ↔

Cmax: ↔

C24h: ↔

OPIOIDS

Methadone/Efavirenz

(35-100 mg q.d./600 mg q.d.)

Methadone:

AUC: ↓ 52% (↓ 33 to ↓ 66)

Cmax: ↓ 45% (↓ 25 to ↓ 59)

(CYP3A4 induction)

In a study of HIV infected intravenous drug users, co-administration of efavirenz with methadone resulted in decreased plasma levels of methadone and signs of opiate withdrawal. The methadone dose was increased by a mean of 22% to alleviate withdrawal symptoms.

Concomitant administration with Efavirenz/Emtricitabine/Tenofovir disoproxil should be avoided due to the risk for QTc prolongation (see section 4.3).

Methadone/Tenofovir disoproxil

(40-110 mg q.d./245 mg q.d.)

Methadone:

AUC: ↔

Cmax: ↔

Cmin: ↔

Tenofovir:

AUC: ↔

Cmax: ↔

Cmin: ↔

Methadone/Emtricitabine

Interaction not studied.

Buprenorphine/naloxone/Efavirenz

Buprenorphine:

AUC: ↓ 50%

Norbuprenorphine:

AUC: ↓ 71%

Efavirenz:

No clinically significant pharmacokinetic interaction.

Despite the decrease in buprenorphine exposure, no patients exhibited withdrawal symptoms. Dose adjustment of buprenorphine may not be necessary when co-administered with Efavirenz/Emtricitabine/Tenofovir disoproxil.

Buprenorphine/naloxone/Emtricitabine

Interaction not studied.

Buprenorphine/naloxone/Tenofovir disoproxil

Interaction not studied.

1 The predominant circulating metabolite of sofosbuvir.

Studies conducted with other medicinal products

There were no clinically significant pharmacokinetic interactions when efavirenz was administered with azithromycin, cetirizine, fosamprenavir/ritonavir, lorazepam, , zidovudine, aluminium/magnesium hydroxide antacids, famotidine or fluconazole. The potential for interactions with efavirenz and other azole antifungals, such as ketoconazole, has not been studied.

There were no clinically significant pharmacokinetic interactions when emtricitabine was administered with stavudine, zidovudine or famciclovir. There were no clinically significant pharmacokinetic interactions when tenofovir disoproxil was co-administered with emtricitabine, or ribavirin.

4.6. Fertility, pregnancy and lactation

Women of childbearing potential (see below and section 5.3)

Pregnancy should be avoided in women receiving Efavirenz/Emtricitabine/Tenofovir disoproxil. Women of childbearing potential should undergo pregnancy testing before initiation of this medicine.

Contraception in males and females

Barrier contraception should always be used in combination with other methods of contraception (for example, oral or other hormonal contraceptives, see section 4.5) while on therapy with Efavirenz/Emtricitabine/Tenofovir disoproxil.

Because of the long half-life of efavirenz, use of adequate contraceptive measures for 12 weeks after discontinuation of Efavirenz/Emtricitabine/Tenofovir disoproxil is recommended.

Pregnancy

Efavirenz: There have been seven retrospective reports of findings consistent with neural tube defects, including meningomyelocele, all in mothers exposed to efavirenz-containing regimens (excluding any efavirenz-containing fixed-dose combination tablets) in the first trimester. Two additional cases (1 prospective and 1 retrospective) including events consistent with neural tube defects have been reported with the fixed-dose combination tablet containing efavirenz, emtricitabine, and tenofovir disoproxil. A causal relationship of these events to the use of efavirenz has not been established, and the denominator is unknown. As neural tube defects occur within the first 4 weeks of foetal development (at which time neural tubes are sealed), this potential risk would concern women exposed to efavirenz during the first trimester of pregnancy.

As of July 2013, the Antiretroviral Pregnancy Registry (APR) has received prospective reports of 904 pregnancies with first trimester exposure to efavirenz-containing regimens, resulting in 766 live births. One child was reported to have a neural tube defect, and the frequency and pattern of other birth defects were similar to those seen in children exposed to non-efavirenz-containing regimens, as well as those in HIV negative controls. The incidence of neural tube defects in the general population ranges from 0.5-1 case per 1,000 live births.

Malformations have been observed in foetuses from efavirenz-treated monkeys (see section 5.3).

Emtricitabine and tenofovir disoproxil: A large amount of data on pregnant women (more than 1,000 pregnancy outcomes) indicates no malformations or foetal/neonatal toxicity associated with emtricitabine and tenofovir disoproxil. Animal studies on emtricitabine and tenofovir disoproxil do not indicate reproductive toxicity (see section 5.3).

Efavirenz/Emtricitabine/Tenofovir disoproxil should not be used during pregnancy unless the clinical condition of the woman requires treatment with efavirenz/emtricitabine/tenofovir disoproxil.

Breast-feeding

Efavirenz, emtricitabine and tenofovir have been shown to be excreted in human milk. There is insufficient information on the effects of efavirenz, emtricitabine and tenofovir in newborns/infants.

A risk to the infants cannot be excluded. Therefore Efavirenz/Emtricitabine/Tenofovir disoproxil should not be used during breast-feeding.

As a general rule, it is recommended that HIV infected women do not breast-feed their infants in order to avoid transmission of HIV to the infant.

Fertility

No human data on the effect of Efavirenz/Emtricitabine/Tenofovir disoproxil are available. Animal studies do not indicate harmful effects of efavirenz, emtricitabine or tenofovir disoproxil on fertility.

4.7. Effects on ability to drive and use machines

No studies on the effects on the ability to drive and use machines have been performed. However, dizziness has been reported during treatment with efavirenz, emtricitabine and tenofovir disoproxil. Efavirenz may also cause impaired concentration and/or somnolence. Patients should be instructed that if they experience these symptoms they should avoid potentially hazardous tasks such as driving and operating machinery.

4.8. Undesirable effects

Summary of the safety profile

The combination of efavirenz, emtricitabine and tenofovir disoproxil has been studied in 460 patients either as the fixed-dose combination tablet (study AI266073) or as the component products (study GS-01-934). Adverse reactions were generally consistent with those seen in previous studies of the individual components. The most frequently reported adverse reactions considered possibly or probably related to the fixed-dose combination of efavirenz/emtricitabine/tenofovir disoproxil among patients treated up to 48 weeks in study AI266073 were psychiatric disorders (16%), nervous system disorders (13%), and gastrointestinal disorders (7%).

Severe skin reactions such as Stevens-Johnson syndrome and erythema multiforme; neuropsychiatric adverse reactions (including severe depression, death by suicide, psychosis-like behaviour, seizures); severe hepatic events; pancreatitis and lactic acidosis (sometimes fatal) have been reported.

Rare events of renal impairment, renal failure and uncommon events of proximal renal tubulopathy (including Fanconi syndrome) sometimes leading to bone abnormalities (infrequently contributing to fractures) have also been reported. Monitoring of renal function is recommended for patients receiving Efavirenz/Emtricitabine/Tenofovir disoproxil (see section 4.4).

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

The administration of Efavirenz/Emtricitabine/Tenofovir disoproxil with food may increase efavirenz exposure and may lead to an increase in the frequency of adverse reactions (see sections 4.4 and 5.2).

Tabulated list of adverse reactions

The adverse reactions from clinical study and post-marketing experience with the fixed-dose combination of efavirenz/emtricitabine/tenofovir disoproxil and the individual components of this medicinal product in antiretroviral combination therapy are listed in Table 2 below by body system organ class, frequency and the component(s) of Efavirenz/Emtricitabine/Tenofovir disoproxil to which the adverse reactions are attributable. 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).

Adverse reactions associated with the use of the fixed-dose combination of efavirenz/emtricitabine/tenofovir disoproxil: Treatment-emergent adverse reactions considered possibly or probably related to the fixed-dose combination of efavirenz/emtricitabine/tenofovir disoproxil reported in study AI266073 (over 48 weeks; n = 203), which have not been associated with one of the individual components of Efavirenz/Emtricitabine/Tenofovir disoproxil , include:

Common:

Uncommon:

- anorexia

- dry mouth

- incoherent speech

- increased appetite

- libido decreased

- myalgia

Table 2: Adverse reactions associated with Efavirenz/Emtricitabine/Tenofovir disoproxil listed by the component(s) of the medicinal product to which the adverse reactions are attributable

Efavirenz/Emtricitabine/Tenofovir disoproxil

Efavirenz

Emtricitabine

Tenofovir disoproxil

Blood and lymphatic system disorders:

Common

neutropenia

Uncommon

anaemia1

Immune system disorders:

Common

allergic reaction

Uncommon

hypersensitivity

Metabolism and nutrition disorders:

Very common

hypophosphataemia2

Common

hypertriglyceridaemia3

hyperglycaemia, hypertriglyceridaemia

Uncommon

hypercholesterolaemia3

hypokalaemia2

Rare

lactic acidosis

Psychiatric disorders:

Common

depression (severe in 1.6%)3, anxiety3, abnormal dreams3, insomnia3

abnormal dreams, insomnia

Uncommon

suicide attempt3, suicide ideation3, psychosis3, mania3, paranoia3, hallucination3, euphoric mood3, affect lability3, confusional state3, aggression3, catatonia3

Rare

completed suicide3,4, delusion3,4, neurosis3,4,

Nervous system disorders:

Very common

headache

dizziness

Common

cerebellar coordination and balance disturbances3, somnolence (2.0%)3, headache (5.7%)3, disturbance in attention (3.6%)3, dizziness (8.5%)3

dizziness

headache

Uncommon

convulsions3, amnesia3, thinking abnormal3, ataxia3, coordination abnormal3, agitation3, tremor

Eye disorders:

Uncommon

vision blurred

Ear and labyrinth disorders:

Uncommon

tinnitus, vertigo

Vascular disorders:

Uncommon

flushing

Gastrointestinal disorders:

Very common

diarrhoea, nausea

diarrhoea, vomiting, nausea

Common

diarrhoea, vomiting, abdominal pain, nausea

elevated amylase including elevated pancreatic amylase, elevated serum lipase, vomiting, abdominal pain, dyspepsia

abdominal pain,abdominal distension, flatulence

Uncommon

pancreatitis

pancreatitis

Hepatobiliary disorders:

Common

elevated aspartate aminotransferase (AST), elevated alanine aminotransferase (ALT), elevated gamma- glutamyltransferase (GGT)

elevated serum AST and/or elevated serum ALT, hyperbilirubinaemia

increased transaminases

Uncommon

hepatitis acute

Rare

hepatic failure3,4

hepatic steatosis, hepatitis

Skin and subcutaneous tissue disorders:

Very common

rash (moderate-severe, 11.6%, all grades, 18%)3

rash

Common

pruritus

vesiculobullous rash, pustular rash, maculopapular rash, rash, pruritus, urticaria, skin discolouration (increased pigmentation)1

Uncommon

Stevens-Johnson syndrome, erythema multiforme3, severe rash (< 1%)

angioedema4

Rare

photoallergic dermatitis

angioedema

Musculoskeletal and connective tissue disorders:

Very common

elevated creatine kinase

Uncommon

rhabdomyolysis2, muscular weakness2

Rare

osteomalacia (manifested as bone pain and infrequently contributing to fractures)2,4, myopathy2

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)4, nephrogenic diabetes insipidus

Reproductive system and breast disorders:

Uncommon

gynaecomastia

General disorders and administration site conditions:

Very common

asthenia

Common

fatigue

pain, asthenia

1 Anaemia was common and skin discolouration (increased pigmentation) was very common when emtricitabine was administered to paediatric patients.

2 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.

3 See section 4.8 Description of selected adverse reactions for more details.

4 This adverse reaction was identified through post-marketing surveillance for either efavirenz, emtricitabine or tenofovir disoproxil. The frequency category was estimated from a statistical calculation based on the total number of patients treated with efavirenz in clinical trials (n = 3,969) or exposed to emtricitabine in randomised controlled clinical trials (n = 1,563) or exposed to tenofovir disoproxil in randomised controlled clinical trials and the expanded access programme (n = 7,319).

Description of selected adverse reactions

Rash: In clinical trials of efavirenz, rashes were usually mild-to-moderate maculopapular skin eruptions that occurred within the first two weeks of initiating therapy with efavirenz. In most patients rash resolved with continuing therapy with efavirenz within one month. Efavirenz/Emtricitabine/Tenofovir disoproxil can be reinitiated in patients interrupting therapy because of rash. Use of appropriate antihistamines and/or corticosteroids is recommended when Efavirenz/Emtricitabine/Tenofovir disoproxil is restarted.

Psychiatric symptoms: Patients with a history of psychiatric disorders appear to be at greater risk of serious psychiatric adverse reactions listed in the efavirenz column of Table 2.

Nervous system symptoms: Nervous system symptoms are common with efavirenz, one of the components of Efavirenz/Emtricitabine/Tenofovir disoproxil. In clinical controlled studies of efavirenz, nervous system symptoms of moderate to severe intensity were experienced by 19% (severe 2%) of patients, and 2% of patients discontinued therapy due to such symptoms. They usually begin during the first one or two days of efavirenz therapy and generally resolve after the first two to four weeks. They may occur more frequently when Efavirenz/Emtricitabine/Tenofovir disoproxil is taken concomitantly with meals possibly due to increased efavirenz plasma levels (see section 5.2). Dosing at bedtime seems to improve the tolerability of these symptoms (see section 4.2).

Hepatic failure with efavirenz: Hepatic failure, including cases in patients with no pre-existing hepatic disease or other identifiable risk factors, as reported post-marketing, were sometimes characterised by a fulminant course, progressing in some cases to transplantation or death.

Renal impairment: As Efavirenz/Emtricitabine/Tenofovir disoproxil may cause renal damage, monitoring of renal function is recommended (see sections 4.4 and 4.8 Summary of the safety profile). Proximal renal tubulopathy generally resolved or improved after tenofovir disoproxil discontinuation. However, in some 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 (see section 4.4).

Lactic acidosis: Cases of lactic acidosis have been reported with tenofovir disoproxil alone or in combination with other antiretrovirals. Patients with predisposing factors such as severe hepatic impairment (CPT, Class C) (see section 4.3), 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.

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 disorders) 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

Insufficient safety data are available for children below 18 years of age. Efavirenz/Emtricitabine/Tenofovir disoproxil is not recommended in this population (see section 4.2).

Other special populations

Elderly: The fixed-dose combination of efavirenz/emtricitabine/tenofovir disoproxil has not been studied in patients over the age of 65. Elderly patients are more likely to have decreased hepatic or renal function, therefore caution should be exercised when treating elderly patients with Efavirenz/Emtricitabine/Tenofovir disoproxil (see section 4.2).

Patients with renal impairment: Since tenofovir disoproxil can cause renal toxicity, close monitoring of renal function is recommended in any patient with mild renal impairment treated with Efavirenz/Emtricitabine/Tenofovir disoproxil (see sections 4.2, 4.4 and 5.2).

HIV/HBV or HCV co-infected patients: Only a limited number of patients were co-infected with HBV (n = 13) or HCV (n = 26) in study GS-01-934. The adverse reaction profile of efavirenz, emtricitabine and tenofovir disoproxil in patients co-infected with HIV/HBV or HIV/HCV 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.

Exacerbations of hepatitis after discontinuation of treatment: In HIV infected patients co-infected with HBV, clinical and laboratory evidence 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 Yellow Card Scheme website www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

Some patients accidentally taking 600 mg efavirenz twice daily have reported increased nervous system symptoms. One patient experienced involuntary muscle contractions.

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

Administration of activated charcoal may be used to aid removal of unabsorbed efavirenz. There is no specific antidote for overdose with efavirenz. Since efavirenz is highly protein bound, dialysis is unlikely to remove significant quantities of it from blood.

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