EFAVIRENZ/EMTRICITABINE/TENOFOVIR DISOPROXIL KRKA

Therapy should be initiated by a physician experienced in the management of HIV infection. Posology Adults The recommended dose of Efavirenz/Emtricitabine/Tenofovir disoproxil Krka is one tablet taken orally once daily. If a patient misses a dose of Efavirenz/Emtricitabine/Tenofovir disoproxil Krka within 12 hours of the time it is usually taken, the patient should take Efavirenz/Emtricitabine/Tenofovir disoproxil Krka as soon as possible and resume the normal dosing schedule.

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

8). 8). 2). Data on the clinical translation of the decrease in pharmacokinetic exposure are not available. 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. 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.

5). 4). Renal impairment Efavirenz/emtricitabine/tenofovir disoproxil is not recommended for patients with moderate or severe renal impairment (creatinine clearance (CrCl) < 50 ml/min). 2). Hepatic impairment The pharmacokinetics of efavirenz/emtricitabine/tenofovir disoproxil have not been studied in patients with hepatic impairment.

2). 4). 4). 2). Method of administration Efavirenz/Emtricitabine/Tenofovir disoproxil Krka tablets should be swallowed whole with water, once daily.

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 efavirenz/emtricitabine/tenofovir disoproxil (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 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.

4). 4). 2). Tabulated list of adverse reactions The adverse reactions from clinical study and post-marketing experience with efavirenz/emtricitabine/tenofovir disoproxil and the individual components of efavirenz/emtricitabine/tenofovir disoproxil 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, adverse reactions 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).

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.

g. 2). 5). Efavirenz/emtricitabine/tenofovir disoproxil should not be administered concomitantly with adefovir dipivoxil or with medicinal products containing tenofovir alafenamide. 5). 5). No data are available on the safety and efficacy of efavirenz/emtricitabine/tenofovir disoproxil in combination with other antiretroviral agents.

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.

8). It is recommended that efavirenz/emtricitabine/tenofovir disoproxil be taken on an empty stomach, preferably at bedtime. 2). 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. 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.

1. 2). Co-administration with terfenadine, astemizole, cisapride, midazolam, triazolam, pimozide, bepridil, or ergot alkaloids (for example, ergotamine, dihydroergotamine, ergonovine, and methylergonovine). 5). Co-administration with elbasvir/grazoprevir due to the expected significant decreases in plasma concentrations of elbasvir and grazoprevir.

5). Co-administration with voriconazole. Efavirenz significantly decreases voriconazole plasma concentrations while voriconazole also significantly increases efavirenz plasma concentrations. 5). Co-administration with herbal preparations containing St.

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.

g. hypokalemia or hypomagnesemia. Co administration with medicinal products that are known to prolong the QTc interval (proarrhythmic). 1).