EFAVIRENZ/EMTRICITABINE/TENOFOVIR DISOPROXIL MACLEODS

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

If a patient misses a dose of Efavirenz/Emtricitabine/Tenofovir disoproxil Macleods 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 Macleods, another tablet should be taken. If the patient vomits more than 1 hour after taking Efavirenz/Emtricitabine/Tenofovir disoproxil Macleods 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 Macleods 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 Macleods 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 Macleods 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 and 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 fixed dose combination of efavirenz, emtricitabine and tenofovir disoproxil and the individual components of this medicine 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 Macleods 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).

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 Common bone mineral density decreased 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 […]

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

g. 2). 5). This medicine 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 Macleods 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 Macleods 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 Macleods 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 Macleods needs to be weighed against the potential risks of significant liver toxicity.

8). In patients treated with other medicinal products associated with liver toxicity, monitoring of liver enzymes is also recommended. 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 efavirenz/emtricitabine/tenofovir disoproxil have not been studied for the treatment of chronic HBV infection.

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 Macleods 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 […]

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 drugs that are known to prolong the QTc interval (proarrhythmic). 1).