Atripla - summary of medicine characteristics

1. NAME OF THE MEDICINAL PRODUCT

Atripla 600 mg/200 mg/245 mg film-coated tablets

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each film-coated tablet contains 600 mg of efavirenz, 200 mg of emtricitabine and 245 mg of tenofovir disoproxil (as fumarate).

For the full list of excipients, see section 6.1

3. PHARMACEUTICAL FORM

Film-coated tablet.

Pink, capsule-shaped, film-coated tablet, of dimensions 20 mm x 10.4 mm, debosse one side, plain on the other side.

4. CLINICAL PARTICULARS4.1 Therapeutic indications

Atripla is a fixed-dose combination of efavirenz, emtricitabine and tenofovir disoproxil fumarate. 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 Atripla prior to initiation of their first antiretroviral treatment regimen (see sections 4.4 and 5.1).

The demonstration of the benefit of Atripla 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 Atripla (see section 5.1). No data are currently available from clinical studies with Atripla in treatment-naïve or in heavily pretreated patients.

4.2 Posology and method of administration

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

The recommended dose of Atripla is one tablet taken orally once daily.

If a patient misses a dose of Atripla within 12 hours of the time it is usually taken, the patient should take Atripla as soon as possible and resume the normal dosing schedule. If a patient misses a dose of Atripla 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 Atripla, another tablet should be taken. If the patient vomits more than 1 hour after taking Atripla he/she does not need to take another dose.

It is recommended that Atripla 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 Atripla 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 Atripla is indicated or where dos modification is necessary, separate preparations of efavirenz, emtricitabine and tenofovir disoprox are available. Please refer to the Summary of Product Characteristics for these medicinal pro

If therapy with Atripla is discontinued, consideration should be given to the long half-li (see section 5.2) and long intracellular half-lives of emtricitabine and tenofovir. interpatient variability in these parameters and concerns regarding development treatment guidelines should be consulted, also taking into consideration the reas

Dose adjustment: If Atripla 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     section 4.5).

Special populations

Elderly

Atripla should be administered with caution to elderly patients (see section 4.4).

tinued in patients co-infected with HIV and HBV, these patients should be closely ence of exacerbation of hepatitis (see section 4.4).

iatric population

safety and efficacy of Atripla in children under the age of 18 years have not been established section 5.2).

Method of administration

Atripla 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 Atripla is a fixed-dose combination product, the dose of efavirenz cannot be altered (see sec

Co-administration with herbal preparations containing St. John’s wort (Hypericum p the risk of decreased plasma concentrations and reduced clinical effects of efavirenz

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 re ant bradycardia or with congestive cardiac failure accompanied by reduced left ventri     ection fraction.

severe disturbances of electrolyte balance e.g. hypokalemi

4.4 Special warnings and precautions for use

Co-administration^th other medicinal products

As a fixe^combination, Atripla should not be administered concomitantly with other medicinal pro        ntaining the same active components, emtricitabine or tenofovir disoproxil. Atripla should

not       dministered with products containing efavirenz unless needed for dose adjustment e.g. with

rifa        (see section 4.2). Due to similarities with emtricitabine, Atripla should not be administered

concomitantly with other cytidine analogues, such as lamivudine (see section 4.5). Atripla should not be administered concomitantly with adefovir dipivoxil or with medicinal products containing tenofovir alafenamide.

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

Co-administration of Atripla 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 of Atripla 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 Atripla 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 Atripla or any other antiretroviral therapy may continue to develop opp infections and other complications of HIV infection, and therefore should remain un observation by physicians experienced in the treatment of patients with HIV associ

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 Atripla with food may increase efavirenz exposure (see section 5.2) and may lead to an increase in frequency of adverse reaction      section 4.8). It is recommended that Atripla

be taken on an empty stomach, preferably at bedtim

Liver disease

The pharmacokinetics, safety and efficacy of Atripla have not been established in patients with significant underlying liver disorders (see section 5.2). Atripla 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 administerin      la to patients with mild hepatic impairment. These patients should be

z adverse reactions, especially nervous system symptoms. Laboratory evaluate their liver disease at periodic intervals (see section 4.2).

Patients with       isting liver dysfunction including chronic active hepatitis have an increased

frequency o nction abnormalities during combination antiretroviral therapy (CART) and

should be       red according to standard practice. If there is evidence of worsening liver disease or

persist t elevations of serum transaminases to greater than 5 times the upper limit of the normal ran     e benefit of continued therapy with Atripla needs to be weighed against the potential risks of

nt liver toxicity. In such patients, interruption or discontinuation of treatment must be

idered (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 Atripla 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 Atripla therapy in patients co-infected with may be associated with severe acute exacerbations of hepatitis. Patients co-infected HBV who discontinue Atripla must be closely monitored with both clinical and labo for at least four months after stopping treatment with Atripla. If appropriate, resump

hepatitis B therapy may be warranted. In patients with advanced liver disease or cir discontinuation is not recommended since post-treatment exacerbation of hepatitis may lead to hepatic decompensation.

QTc Prolongation

cluding, but not limited to, dizziness, insomnia, somnolence, impaired concentration and aming are frequently reported undesirable effects in patients receiving efavirenz 600 mg al studies. Dizziness was also seen in clinical studies with emtricitabine and tenofovir il. Headache has been reported in clinical studies with emtricitabine (see section 4.8). system symptoms associated with efavirenz usually begin during the first one or two days of py 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 a drug 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

Atripla 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 Atripla should be avoided with concurrent or recent use of a nephrotoxic medicinal product. If concomitant use of Atripla 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-inflam drugs (NSAIDs) have been reported in patients treated with tenofovir disoproxil and with for renal dysfunction. If Atripla is co-administered with an NSAID, renal function s monitored adequately.

Renal failure, renal impairment, elevated creatinine, hypophosphataemia and pro      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 pati Atripla and renal function (creatinine clearance and serum pho four weeks of treatment, after three months of treatment and ev patients without renal risk factors. In patients with a his are at risk of renal dysfunction, a more frequent monito

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).

fovir disoproxil may also cause a reduction in bone mineral density (BMD). In a 144-week olled clinical study that compared tenofovir disoproxil with stavudine in combination with ivudine and efavirenz in antiretroviral-naive 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 Atripla. 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 1% of patients treated with efavirenz (see section 4.8). The incidence of erythema multiforme or Stevens-Johnson syndrome was approximately 0.1%. Atripla must be discontinued in patient developing severe rash associated with blistering, desquamation, mucosal involvement or Experience with efavirenz in patients who discontinued other antiretroviral agents of is limited. Atripla is not recommended for patients who have had a life-threatenin (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 o therapy. Such changes may in part be linked to disease control and li some cases evidence for a treatment effect, while for weight gai this to any particular treatment. For monitoring of blood lipids an

established HIV treatment guidelines. Lipid

Mitochondrial dysfunction following exposure in uh

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 recomm     ions to use antiretroviral therapy in pregnant women to prevent vertical

transmission o

Immune ^^CtiVation Syndrome

In      nfected patients with severe immune deficiency at the time of institution of CART, an

atory reaction to asymptomatic or residual opportunistic pathogens may arise and cause ious 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

Atripla should be avoided in patients with HIV-1 harbouring the K65R, M184V/I or K103N mutatio (see sections 4.1 and 5.1).

Elderly

Atripla has not been studied in patients over the age of 65. Elderly patients are more decreased hepatic or renal function, therefore caution should be exercised when treat patients with Atripla (see section 4.2).

4.5 Interaction with other medicinal products and other forms of interaction

As Atripla contains efavirenz, emtricitabine and tenofovir disoproxil, identified with these agents individually may occur with Atripla. have only been performed in adults.

As a fixed combination, Atripla should not be administe products containing the components, emtricitabine or te

administered with products containing efavirenz un rifampicin (see section 4.2). Due to similarities w concomitantly with other cytidine analogues, s

concomitantly with adefovir dipivoxil or with medicinal products containing tenofovir alafenamide.

Efavirenz is an in vivo inducer of CY YP2B6 and UGT1A1. Compounds that are substrates of

these enzymes may have decreased p 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 /^Clinical efficacy. Therefore, caution is advised when metamizole and efavirenz are admmjsteredwoncurrently; clinical response and/or drug levels should be monitored as appropriate.

osure may be increased when given with medicinal products (for example ritonavir) or xample, grapefruit juice) which inhibit CYP3A4 or CYP2B6 activity. Compounds or reparations (for example Ginkgo biloba extracts and St. John’s wort) which induce these es 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

Atripla 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 Atripla with elbasvir/grazoprevir is contraindicated because it may lead to loss of virologic response to elbasvir/grazoprevir (see section 4.3 and Tabl

Voriconazole: Co-administration of standard doses of efavirenz and voriconazole is contraind Since Atripla is a fixed-dose combination product, the dose of efavirenz cannot be a voriconazole and Atripla must not be co-administered (see section 4.3 and Table 1).

St. John’s wort (Hypericum perforatum): Co-administration of Atripla and St. Jo

preparations containing St. John’s wort is contraindicated. Plasma levels of e by concomitant use of St. John’s wort due to induction of drug metabolising e proteins by St. John’s wort. If a patient is already taking St. John’s wort, stop viral levels and if possible efavirenz levels. Efavirenz levels may inc wort. The inducing effect of St. John’s wort may persist for at lea treatment (see section 4.3).

QT Prolonging Drugs: Atripla is contraindicated with concomitant use of drugs 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, certai tibiotics including some agents of the following classes: macrolides, fluoroquinolones, imi ole, and triazole antifungal agents, certain non-sedating antihistaminics (terfenadine, aste ole), cisapride, flecainide, certain antimalarials and methadone (see section 4.3).

Atazanavir/ritonavir: Insufficient data are available to make a dosing recommendation for atazanavir/ritonavir in combination with Atripla. Therefore co-administration of atazanavir/ritonavir and Atripla is not recomm d (see Table 1).

on of Atripla and didanosine is not recommended (see Table 1).

Sofosbuvir/velpatasvir and sofosbuvir/velpatasvir/voxilaprevir : Co-administration of Atripla and sofosbuvir/velpatasvir or sofosbuvir/velpatasvir/voxilaprevir is not recommended (see section 4.4 and

Table 1) iminated medicinal products: Since emtricitabine and tenofovir are primarily eliminated by idneys, co-administration of Atripla with medicinal products that reduce renal function or ete for active tubular secretion (e.g. cidofovir) may increase serum concentrations of tricitabine, tenofovir and/or the co-administered medicinal products.

Use of Atripla 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 Atripla 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.”,

0$

Diltiazem/Emtridtabine

Diltiazem/Tenofovir disoproxil _______

Verapamil, Felodipine, Nifedipine and Nicardipine

(CYP3A4

The increase in efavirenz pharma ic parameters is not

conside clinically significant. __________

Interaction not studied. _________________________

interaction not studied. ________________

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.

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.

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 Atripla.

Because of the long half-life of efavirenz, use of adequate contraceptive measures for 12 weeks after dis

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 1000 pregnancy outcomes) indicates no malformations or foetal/neonatal toxicity associated with emtricitabine and tenofovir disoproxil. Animal studies on emtricitabine and tenofovir disoproxil not indicate reproductive toxicity (see section 5.3).

Atripla should not be used during pregnancy unless the clinical condition of the woman re 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 Atripla should no sed during breast-feeding.

As a general rule, it is recommended that HIV infected women to avoid transmission of HIV to the infant.

Fertility

No human data on the effect of Atripla 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 us

No studies on the effects on the abili rive 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.

ion of efavirenz, emtricitabine and tenofovir disoproxil has been studied in 460 patients as the fixed-dose combination tablet Atripla (study AI266073) or as the component products GS-01–934). Adverse reactions were generally consistent with those seen in previous studies of dividual components. The most frequently reported adverse reactions considered possibly or probably related to Atripla 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 Atripla (see section 4.4).

Discontinuation of Atripla 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 Atripla 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 Atripla and the individual components of Atripla in antiretroviral combination therapy are listed in Table 2 below by body system organ class, frequency and the component(s) of Atripla 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^/TW) uncommon (> 1/1,000 to < 1/100) or rare (> 1/10,000 to < 1/1,000).

Adverse reactions associated with the use of Atripla: Treatment-emergent adverse reactions considered possibly or probably related to Atripla reported in study AI266073 (over 48 weeks; n = 203), which have not been associated with one of the individual components of Atripla, include:

Common:     -    anorexia

incoherent speech increased appetite libido decreased myalgia

Table 2: Adverse reactions associated with Atripla listed by the component(s) of Atripla to which the adverse reactions are attributable

t safety data are available for children below 18 years of age. Atripla is not recommended is population (see section 4.2).

>ther special populations

Elderly: Atripla 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 Atripla (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 Atripla (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

It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthca professionals are asked to report any suspected adverse reactions via the national re listed in

4.9 Overdose

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

If overdose occurs, the patient must be monitored for evidence 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.

tely 10% of the tenofovir dose can be removed by

haemodialysis. It is not known whether emtricitabine or tenofovir can be removed by peritoneal dialysis.

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Antiviral for systemic use, antivirals for treatment of HIV infections, combinations, ATC code: J05AR06

and pharmacodynamic effects is an NNRTI of HIV-1. Efavirenz non-competitively inhibits HIV-1 reverse transcriptase does not significantly inhibit human immunodeficiency virus-2 (HIV-2) RT or cellular OXyribonucleic acid (DNA) polymerases (a, P, y, and 3). Emtricitabine is a nucleoside analogue of cytidine. Tenofovir disoproxil is converted in vivo to tenofovir, a nucleoside monophosphate (nucleotide) analogue of adenosine monophosphate.

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

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

Cardiac Electrophysiology

The effect of efavirenz on the QTc interval was evaluated in an open-label, positive and placebo controlled, fixed single sequence 3-period, 3-treatment crossover QT study in 58 healthy subjects enriched for CYP2B6 polymorphisms. The mean Cmax of efavirenz in subjects with CYP2B6 6/6 genotype following the administration of 600 mg daily dose for 14 days was 2.25-fold the mean Cmax observed in subjects with CYP2B6 1/1 genotype. A positive relationship between efavirenz concentration and QTc prolongation was observed. Based on the concentration-QTc relationshi mean QTc prolongation and its upper bound 90% confidence interval are 8.7 ms and 11.3 ms in subjects with CYP2B66/6 genotype following the administration of 600 mg daily dose for 14 (see section 4.5).

Antiviral activity in vitro

Efavirenz demonstrated antiviral activity against most non-clade B isolates (subtypes A, AE, AG, C, D, F, G, J, and N) but had reduced antiviral activity against group O viruses. Emtricitabine displayed antiviral activity against HIV-1 clades A, B, C, D, E, F, and G. Tenofovir displayed antiviral activity against HIV-1 clades A, B, C, D, E, F, G, and O. Both emtricitabine and tenofovir showed strain specific activity against HIV-2 and antiviral activity against HBV.

mtricitabine or tenofovir has been seen in vitro and in some HIV-1 infected patients due nt of an M184V or M184I substitution in RT with emtricitabine or a K65R

RT with tenofovir. Emtricitabine-resistant viruses with the M184V/I mutati­on were

tant to lamivudine, but retained sensitivity to didanosine, stavudine, tenofovir and

ine. The K65R mutation can also be selected by abacavir or didanosine and results in reduced ptibility to these agents plus lamivudine, emtricitabine and tenofovir. Tenofovir disoproxil should be avoided in patients with HIV-1 harbouring the K65R mutation. Both the K65R and M184V/I mutation remain fully susceptible to efavirenz. In addition, a K70E substitution in HIV-1 RT has been selected by tenofovir and results in low-level reduced susceptibility to abacavir, emtricitabine, lamivudine and tenofovir.

Patients with HIV-1 expressing three or more thymidine analogue associated mutations (TAMs) that included either an M41L or an L210W substitution in RT showed reduced susceptibility to tenofovir disoproxil.

In vivo resistance (antiretroviral-naivepatients): In a 144-week open-label randomised clinical study (GS-01–934) in antiretroviral-naive patients, where efavirenz, emtricitabine and tenofovir disoproxil were used as individual formulations (or as efavirenz and the fixed combination of emtricitabine and tenofovir disoproxil (Truvada) from week 96 to 144), genotyping was performed on plasma

HIV-1 isolates from all patients with confirmed HIV RNA > 400 copies/ml at week 144 or early study drug discontinuation (see section on Clinical experience ). As of week 144:

The M184V/I mutation developed in 2/19 (10.5%) isolates analysed from patients in the

efavirenz + emtricitabine + tenofovir disoproxil group and in 10/29 (34.5%) isolates analysed from the efavirenz + lamivudine/zi­dovudine group (p-value < 0.05, Fisher’s Exact test comparing the emtricitabine + tenofovir disoproxil group to the lamivudine/zi­dovudine group among all subjects).

No virus analysed contained the K65R or K70E mutation.

Genotypic resistance to efavirenz, predominantly the K103N mutation, developed in vi

Please refer to the Summary of Product Characteristics for the individual components for additional information regarding in vivo resistance with these medicinal products.

Clinical efficacy and safety

In a 144-week open-label randomised clinical study (GS-01–934) antiretroviral treatment-naive HIV-1 infected patients received either a once-daily regimen of efavirenz, emtricitabine and tenofovir disoproxil or a fixed combination of lamivudine and zidovudine (Combivir) administered twice daily and efavirenz once daily (please refer to the Summary of Product Characteristics for Truvada). Patients who completed 144 weeks of treatment with either treatment arm in study GS-01–934 were given the option to continue in an open-label extended phase of the study with Atripla on an empty stomach. Data are available from 286 patients who switched to Atripla: 160 had previously received efavirenz, emtricitabine and tenofovir disoproxil, and 126 had previously received Combivir and efavirenz. High rates of virologic suppression were maintained by subjects from both initial treatme groups who then received Atripla in the open-label extended phase of the study. After 96 weeks of

When the two strata were analysed separately, response rates in the stratum with prior PI-treatment were numerically lower for patients switched to Atripla [92.4% versus 94.0% for the PVR (sensitivity analysis) for Atripla and SBR patients respectively; a difference (95%CI) of –1.6% (-10.0%, 6.7%). In the prior-NNRTI stratum, response rates were 98.9% vs 97.4% for Atripla and SBR patients respectively; a difference (95%CI) of 1.4% (-4.0%, 6.9%)].

A similar trend was observed in a sub-group analysis of treatment-experienced patients with baseline HIV-1 RNA < 75 copies/ml from a retrospective cohort study (data collected over 20 months, see Table 5).

No data are currently available from clinical studies with Atripla in treatment-naive patients or in heavily pretreated patients. There is no clinical experience with Atripla in patients who are experiencing virological failure in a first-line antiretroviral treatment regimen or in combinatio other antiretroviral agents.

Patients coinfected with HIV and HBV

Limited clinical experience in patients co-infected with HIV and HBV suggests tha       ent with

emtricitabine or tenofovir disoproxil in antiretroviral combination therapy to control HIV infection also results in a reduction in HBV DNA (3 log10 reduction or 4 to 5 log10 reduction, respectively) (see section 4.4).

Paediatric population

The safety and efficacy of Atripla in children under the a

5.2 Pharmacokinetic properties

The separate pharmaceutical forms of efavirenz, emtricitabine and tenofovir disoproxil were used to determine the pharmacokinetics of efavirenz, emtricitabine and tenofovir disoproxil, administered separately in HIV infected patients. The bioequivalence of one Atripla film-coated tablet with one efavirenz 600 mg film-coated tablet plus     mtricitabine 200 mg hard capsule plus one tenofovir

disoproxil 245 mg film-coated tab           nt to 300 mg tenofovir disoproxil fumarate)

administered together, was establi         wing single dose administration to fasting healthy subjects

in study GS-US-177–0105 (see Ta

inetic data from study GS-US-177–0105

Test: single fixed-dose combination tablet taken under fasted conditions.

Reference: single dose of a 600 mg efavirenz tablet, 200 mg emtricitabine capsule and 300 mg tenofovir disoproxil tablet taken under fasted conditions.

Values for Test and Reference are mean (% coefficient of variation). GMR=geometric least-squares mean ratio, CI=confidence interval

icitabine to human plasma proteins is < 4% and independent of concentrations o 200 tg/ml. Following intravenous administration the volume of distribution

s approximately 1.4 l/kg. After oral administration, emtricitabine is widely

hout the body. The mean plasma to blood concentration ratio was approximately 1.0

semen to plasma concentration ratio was approximately 4.0.

inding of tenofovir to human plasma or serum protein is < 0.7% and 7.2%, respectively over nofovir concentration range 0.01 to 25 tg/ml. Following intravenous administration the volume of distribution of tenofovir was approximately 800 ml/kg. After oral administration, tenofovir is widely distributed throughout the body.

Biotransformation

Studies in humans and in vitro studies using human liver microsomes have demonstrated that efavirenz is principally metabolised by the CYP system to hydroxylated metabolites with subsequent glucuronidation of these hydroxylated metabolites. These metabolites are essentially inactive against HIV-1. The in vitro studies suggest that CYP3A4 and CYP2B6 are the major isozymes responsible for efavirenz metabolism and that it inhibits CYP isozymes 2C9, 2C19, and 3A4. In in vitro studies efavirenz did not inhibit CYP2E1 and inhibited CYP2D6 and CYP1A2 only at concentrations well above those achieved clinically.

Efavirenz plasma exposure may be increased in patients with homozygous G516T genetic variant of the CYP2B6 isozyme. The clinical implications of such an association are unknown; however, the potential for an increased frequency and severity of efavirenz-associated adverse events cannot be excluded.

Efavirenz has been shown to induce CYP3A4 and CYP2B6, resulting in the induction of its own metabolism, which may be clinically relevant in some patients. In uninfected volunteers, multiple doses of 200 to 400 mg per day for 10 days resulted in a lower than predicted extent of accumulation (22 to 42% lower) and a shorter terminal half-life of 40 to 55 hours (single dose half-life 52 to 76 hours). Efavirenz has also been shown to induce UGT1A1. Exposures of raltegravir (a UG substrate) are reduced in the presence of efavirenz (see section 4.5, Table 1). Although in vitr suggest that efavirenz inhibits CYP2C9 and CYP2C19, there have been contradictory reports o increased and decreased exposures to substrates of these enzymes when co-administ efavirenz in vivo. The net effect of co-administration is not clear.

There is limited metabolism of emtricitabine. The biotransformation of emtricit      ncludes

oxidation of the thiol moiety to form the 3'-sulphoxide diastereomers (approximately 9% of dose) and

conjugation with glucuronic acid to form 2'-O-glucuronide (approximate studies have determined that neither tenofovir disoproxil nor tenofovi

CYP enzymes. Neither emtricitabine nor tenofovir inhibited in vit any of the major human CYP isoforms involved in drug biotra not inhibit uridine 5'-diphosphoglucuronyl transferase, the e

Elimination

Efavirenz has a relatively long terminal half-life of at least 52 hours after single doses (see also data

from bioequivalence study described above) an

14 to 34% of a radiolabelled dose of efavirenz was recovered in the urine and less than 1% of the dose was excreted in urine as unchanged efavirenz.

Following oral administration, the el      ion half-life of emtricitabine is approximately 10 hours.

Emtricitabine is primarily excreted by the kidneys with complete recovery of the dose achieved in urine (approximately 86%) and faeces (approximately 14%). Thirteen percent of the emtricitabine dose was recovered in urine as three metabolites. The systemic clearance of emtricitabine averaged 307 ml/min.

ration, the elimination half-life of tenofovir is approximately 12 to 18 hours.

excreted by the kidneys by both filtration and an active tubular transport system

70 to 80% of the dose excreted unchanged in urine following intravenous

e apparent clearance of tenofovir averaged approximately 307 ml/min. Renal

een estimated to be approximately 210 ml/min, which is in excess of the glomerular te. This indicates that active tubular secretion is an important part of the elimination of armacokinetics in special populations

Age

Pharmacokinetic studies have not been performed with efavirenz, emtricitabine or tenofovir in elderly patients (over 65 years of age).

Gender

The pharmacokinetics of emtricitabine and tenofovir are similar in male and female patients. Limited data suggest that females may have higher exposure to efavirenz but they do not appear to be less tolerant of efavirenz.

Ethnicity

Limited data suggest that Asian and Pacific Island patients may have higher exposure to efavirenz but they do not appear to be less tolerant of efavirenz.

Paediatric population

Pharmacokinetic studies have not been performed with Atripla in infants and children under 18 years of age (see section 4.2).

Renal impairment

The pharmacokinetics of efavirenz, emtricitabine and tenofovir disoproxil after co-administration of the separate pharmaceutical forms or as Atripla have not been studied in HIV infected patients wi renal impairment.

Pharmacokinetic parameters were determined following administration of single doses of the individual preparations of emtricitabine 200 mg or tenofovir disoproxil 245 mg to n patients with varying degrees of renal impairment. The degree of renal impairment according to baseline creatinine clearance (normal renal function when creatinine clearance > 80 ml/min; mild impairment with creatinine clearance=50 to 79 ml/min; moderate impairment with creatinine clearance=30 to 49 ml/min and severe impairment with creatinine clearance=10 to 29 ml/min).

The mean (%CV) emtricitabine exposure increased from 12 ^g^h/ renal function to 20 ^g^h/ml (6%), 25 ^g^h/ml (23%) and 34 ^ moderate and severe renal impairment, respectively.

The mean (%CV) tenofovir exposure increased from 2,185     /ml (12%) in patients with normal

renal function, to 3,064 ng^h/ml (30%), 6,009 ng^h/mh(42%) and 15,985 ng^h/ml (45%) in patients with mild, moderate and severe renal impairment, respectively.

In patients with end-stage renal disease (ESRD) requiring haemodialysis, between dialysis drug exposures substantially increased over 7 r^to 53 ^g^h/ml (19%) of emtricitabine, and over

48 hours to 42,857 ng^h/ml (29%^

The pharmacokinetics of efavirenz have not been studied in patients with renal impairment. However, less than 1% of an efavirenz dose is excreted unchanged in the urine, so the impact of renal impairment on exposure to efavirenz is likely to be minimal.

for patients with moderate or severe renal impairment

l/min). Patients with moderate or severe renal impairment require dose emtricitabine and tenofovir disoproxil that cannot be achieved with the e sections 4.2 and 4.4).

irment

okinetics of Atripla have not been studied in HIV infected patients with hepatic

impairment. Atripla should be administered with caution to patients with mild hepatic impairment (see sections 4.3 and 4.4).

Atripla must not be used in patients with severe hepatic impairment (see section 4.3) and is not recommended for patients with moderate hepatic impairment. In a single-dose study of efavirenz, half-life was doubled in the single patient with severe hepatic impairment (Child-Pugh-Turcotte

Class C), indicating a potential for a much greater degree of accumulation. A multiple-dose study of efavirenz showed no significant effect on efavirenz pharmacokinetics in patients with mild hepatic impairment (Child-Pugh-Turcotte Class A) compared with controls. There were insufficient data to determine whether moderate or severe hepatic impairment (Child-Pugh-Turcotte Class B or C) affects efavirenz pharmacokinetics.

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

A single 245 mg dose of tenofovir disoproxil was administered to non-HIV infected patients with varying degrees of hepatic impairment defined according to CPT classification. Tenofovir pharmacokinetics were not substantially altered in subjects with hepatic impairment suggesting that no dose adjustment of tenofovir disoproxil is required in these subjects.

5.3 Preclinical safety data

Efavirenz : Non-clinical safety pharmacology studies on efavirenz reveal no special hazard for hu

In repeated-dose toxicity studies, biliary hyperplasia was observed in cynomolgus monkeys gi efavirenz for > 1 year at a dose resulting in mean AUC values approximately 2-fold greater th in humans given the recommended dose. The biliary hyperplasia regressed upon cessation o

Biliary fibrosis has been observed in rats. Non-sustained convulsions were observed i receiving efavirenz for > 1 year, at doses yielding plasma AUC values 4– to 13-fold in humans given the recommended dose.

Efavirenz was not mutagenic or clastogenic in conventional genotoxicity assays. Carcinogenicity studies showed an increased incidence of hepatic and pulmonary tumours in female mice, but not in male mice. The mechanism of tumour formation and the potential relevance for humans are not known. Carcinogenicity studies in male mice, male and female rats were negative.

Reproductive toxicity studies showed increased foetal re observed in foetuses from efavirenz-treated rats and rabb in 3 of 20 foetuses/new­borns from efavirenz-treated cyn

plasma efavirenz concentrations similar to those seen in humans. Anencephaly and unilateral anophthalmia with secondary enlargement of the tongue were observed in one foetus, microophthalmia was observed in another foetus and cleft palate was observed in a third foetus.

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

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

Combination of emtricitabine and tenofovir disoproxil : Genotoxicity and repeated-dose toxicity studies of one month or less with the combination of these two components found no exacerbation of toxicological effects compared to studies with the separate components.

6. PHARMACEUTICAL PARTICULARS6.1 List of excipients

Tablet core

Croscarmellose sodium

Hyprolose

Magnesium stearate (E572)

Microcrystalline cellulose (E460)

Sodium laurilsulfate

Store in the original package in order to protect from moisture. Keep the bottle tightly closed.

6.5 Nature and contents of container

High density polyethylene (HDPE) bottle with a polypropylene child-resistant closure containing

d silica gel desiccant.

The following pack sizes are available: outer cartons containing 1 bottle of 30 film-coated tablets and

0) film-coated tablets

6.6 Special precautions for disposal

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

7. MARKETING AUTHORISATION HOLDER

Gilead Sciences Ireland UC

Carrigtohill

County Cork, T45 DP77

Ireland

8. MARKETING AUTHORISATION NUMBER(S)

EU/1/07/430/001

EU/1/07/430/002

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 13 December 2007

Date of latest renewal: 17 September 2012