Emtritaf 200/25 200 /25 mg FC tablets

Emtritaf 200/25 is indicated in combination with other antiretroviral medicines for the treatment of adults and adolescents (aged 12 years and older with body weight at least 35 kg) infected with human immunodeficiency virus type 1 (HIV-1) (see sections 4.2 and 5.1).

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

Posology:

Adults and adolescents aged 12 years and older, weighing at least 35 kg

Emtritaf 200/25 should be administered as shown in Table 1.

Table 1: Dose of Emtritaf 200/25 according to third agent in the HIV treatment regimen

Dose of Emtritaf 200/25 Third medicine in HIV treatment regimen (see section 4.5) Emtritaf 200/25 200/25 mg once daily Dolutegravir, efavirenz, maraviroc, nevirapine, rilpivirine, raltegravir

If the patient misses a dose of Emtritaf 200/25 within 18 hours of the time it is usually taken, the patient should take Emtritaf 200/25 as soon as possible and resume the normal dosing schedule. If a patient misses a dose of Emtritaf 200/25 by more than 18 hours, the patient should not take the missed dose and simply resume the usual dosing schedule. If the patient vomits within 1 hour of taking Emtritaf 200/25 another tablet should be taken.

Special populations

Elderly: No dose adjustment of Emtritaf 200/25 is required in elderly patients (see sections 5.1 and 5.2).

Renal impairment: No dose adjustment of Emtritaf 200/25 is required in adults or adolescents (aged at least 12 years and of at least 35 kg body weight) with estimated creatinine clearance (CrCl) u2265 30 mL/min. Emtritaf 200/25 should be discontinued in patients with estimated CrCl that declines below 30 mL/min during treatment (see sections 4.4 and 5.2). No dose adjustment of Emtritaf 200/25 is required in adults with end stage renal disease (estimated CrCl < 15 mL/min) on chronic haemodialysis; however, Emtritaf 200/25 should generally be avoided but may be used in these patients (see sections 4.4 and 5.2). On days of haemodialysis, Emtritaf 200/25 should be administered after completion of haemodialysis treatment. Emtritaf 200/25 should be avoided in patients with estimated CrCl u2265 15 mL/min and < 30 mL/min as the safety of Emtritaf 200/25 has not been established in this population. Emtritaf 200/25 should not be used in patients with CrCl < 15 mL/min who are not receiving haemodialysis (see section 4.4). No data are available to make dose recommendations in children less than 18 years with end stage renal disease.

Hepatic impairment: No dose adjustment of Emtritaf 200/25 is required in patients with mild to moderate hepatic impairment. Emtritaf 200/25 has not been studied in patients with severe hepatic impairment (Child-Pugh Class C); therefore, Emtritaf 200/25 is not recommended for use in patients with severe hepatic impairment as no dose recommendations can be made (see sections 4.4 and 5.2).

Paediatric population: The safety and efficacy of Emtritaf 200/25 in children younger than 12 years of age, or weighing < 35 kg, have not been established. No data are available.

Method of administration: Emtritaf 200/25 should be taken orally, once daily with or without food (see section 5.2). The film-coated tablet should not be chewed, crushed, or split.

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

While effective viral suppression with antiretroviral therapy has been proven to reduce the risk of sexual transmission or blood contamination, the risk of transmission remains present. Precautions to prevent transmission should be taken in accordance with national guidelines.

Patients co-infected with HIV and hepatitis B or C virus: Patients with chronic hepatitis B or C treated with antiretroviral therapy are at an increased risk for severe and potentially fatal hepatic adverse reactions. The safety and efficacy of Emtritaf 200/25 in patients co-infected with HIV-1 and hepatitis C virus (HCV) have not been established. Tenofovir alafenamide is active against hepatitis B virus (HBV). Discontinuation of Emtritaf 200/25 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 Emtritaf 200/25 should be closely monitored with both clinical and laboratory follow-up for at least several months after stopping treatment. In patients with advanced liver disease or cirrhosis, treatment discontinuation is not recommended since post treatment exacerbation of hepatitis may lead to hepatic decompensation.

Liver disease: Use of Emtritaf 200/25 can result in hepatomegaly due to non-alcoholic fatty liver disease (hepatic steatosis). The safety and efficacy of Emtritaf 200/25 has not been established in patients with significant underlying liver disorders/diseases. In case of concomitant antiviral therapy for hepatitis B or C, please also consult the Professional Information of these medicines. Patients with pre-existing liver dysfunction including chronic active hepatitis have an increased frequency of liver function abnormalities during combination antiretroviral therapy and should be monitored. If there is evidence of worsening liver disease in such patients, temporary or permanent discontinuation of treatment must be considered.

Weight and metabolic parameters: An increase in weight and in levels of blood lipids (hyperlipidaemia) and glucose may occur during antiretroviral therapy. Such changes may in part be linked to disease control and lifestyle. 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 have been demonstrated in vitro and in vivo to cause a variable degree of mitochondrial dysfunction/damage. There have been reports of mitochondrial dysfunction in HIV negative infants exposed in utero and/or postnatally to nucleoside analogues. Manifestations of mitochondrial dysfunction include haematological disorders (anaemia, neutropenia), peripheral neuropathy and metabolic disorders (hyperlactataemia, lactic acidosis, hyperlipasaemia). Late onset neurological disorders have been reported (hypertonia, convulsion, abnormal behaviour). Whether such neurological disorders are transient or permanent is unknown.

Possible mitochondrial dysfunction should be considered in any newborn/infant/child exposed in utero to nucleos(t)ide analogues, including HIV negative infants/children who present with severe clinical findings of unknown aetiology, particularly neurologic findings. These babies/infants and children should have clinical and laboratory follow up and be fully investigated for possible mitochondrial dysfunction.

Lactic acidosis: Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues, including emtricitabine, a component of Emtritaf 200/25, and tenofovir DF, another prodrug of tenofovir, alone or in combination with other antiretrovirals. Treatment with Emtritaf 200/25 should be suspended in any individual who develops clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity (which may include hepatomegaly and steatosis even in the absence of marked transaminase elevations). Clinical features of lactic acidosis are non-specific and include nausea, vomiting, abdominal pain, dyspnoea, fatigue and weight loss. In patients with suspicious symptoms or biochemistry, measure the venous lactate level (normal < 2mmol/L), and the serum bicarbonate and respond as follows:

• Lactate 2-5 mmol/L with minimum symptoms: switch to medicines that are less likely to cause lactic acidosis
• Lactate 5-10 mmol/L with symptoms and/or with reduced standard bicarbonate. Stop NRTIs and change treatment option. Once the lactate has settled, use medicines that are less likely to cause lactic acidosis.
• Exclude other causes (e.g. sepsis, uraemia, diabetic keto acidosis, thyrotoxicosis/hyperthyroidism)
• Lactate > 10mmol/L. STOP all therapy (80% mortality)

The above values may not be applicable to paediatric patients. Caution should be exercised when administering Emtritaf 200/25 to patients with known risk factors for liver disease.

Immune Reactivation Syndrome (IRS) / Immune Reconstitution Inflammatory Syndrome (IRIS): Immune Reactivation Syndrome (IRS) is an immunopathological response resulting from the rapid restoration of pathogen-specific immune responses to pre-existing antigens combined with immune dysregulation, which occurs shortly after starting combination antiretroviral therapy (CART). Typically, such reaction presents by paradoxical deterioration of opportunistic infections being treated or with unmasking of asymptomatic opportunistic disease, often with an atypical inflammatory presentation. IRS usually develops within the first 3 months of initiation of ART and occurs more commonly in patients with low CD4+ counts. Relevant examples include cytomegalovirus retinitis, generalised and/or focal mycobacterial and other infections, such as tuberculosis, cryptococcal meningitis and Pneumocystis jirovecii pneumonia. Appropriate treatment of the opportunistic disease(s) should be instituted or continued, and ART continued. Inflammatory manifestations generally subside after a few weeks. Severe cases may respond to glucocorticoids, but there is only limited evidence for this in patients with tuberculosis IRS.

Autoimmune disorders (such as Gravesu2019 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.

Patients with HIV-1 harbouring mutations: Emtritaf 200/25 should not be started in antiretroviral-experienced patients with HIV-1 harbouring the K65R mutation (see section 5.1).

Triple nucleoside therapy: There have been reports of a high rate of virological failure and of emergence of resistance at an early stage when tenofovir disoproxil was combined with lamivudine and abacavir as well as with lamivudine and didanosine as a once daily regimen. Therefore, the same problems may be seen if Emtritaf 200/25 is administered with a third nucleoside analogue.

Opportunistic infections: Patients receiving Emtritaf 200/25 should be advised that they may continue to develop opportunistic infections and other complications of HIV infection, and therefore they should remain under close observation by healthcare professionals experienced in the treatment of patients with associated HIV disease. Regular monitoring of viral load and CD4 counts needs to be done.

Osteonecrosis: Although the aetiology 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.

Nephrotoxicity: A potential risk of nephrotoxicity resulting from chronic exposure to low levels of tenofovir due to dosing with tenofovir alafenamide cannot be excluded (see section 5.3).

Patients with end stage renal disease on chronic haemodialysis: Emtritaf 200/25 should generally be avoided but may be used in adults with end stage renal disease (estimated CrCl < 15 ml/min) on chronic haemodialysis with close monitoring for the risks (see section 4.2). In a study of emtricitabine + tenofovir alafenamide in combination with elvitegravir + cobicistat as a fixed-dose combination tablet (E/C/F/TAF) in HIV-1 infected adults with end stage renal disease (estimated CrCl < 15 ml/min) on chronic haemodialysis, efficacy was maintained through 48 weeks but emtricitabine exposure was significantly higher than in patients with normal renal function. Although there were no new safety issues identified, the implications of increased emtricitabine exposure remain uncertain (see sections 4.8 and 5.2).

Co-administration of other medicines: The co-administration of Emtritaf 200/25 is not recommended with certain anticonvulsants (e.g., carbamazepine, oxcarbazepine, phenobarbitone and phenytoin), antimycobacterials (e.g., rifampicin, rifabutin, rifapentine), boceprevir, St. Johnu2019s wort and HIV protease inhibitors (PIs) other than atazanavir, lopinavir and darunavir (see section 4.5). Emtritaf 200/25 should not be administered concomitantly with medicines containing tenofovir alafenamide, tenofovir disoproxil, emtricitabine, lamivudine or adefovir dipivoxil.

Interaction studies have only been performed in adults.

Emtricitabine: In vitro and clinical pharmacokinetic interaction studies have shown that the potential for CYP-mediated interactions involving emtricitabine with other medicines is low. Co-administration of emtricitabine with medicines that are eliminated by active tubular secretion may increase concentrations of emtricitabine, and/or the co-administered medicine. Medicines that decrease renal function may increase concentrations of emtricitabine.

Tenofovir alafenamide: Tenofovir alafenamide is transported by P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP). Medicines that strongly affect P-gp and BCRP activity may lead to changes in tenofovir alafenamide absorption. Medicines that induce P-gp activity (e.g., rifampicin, rifabutin, carbamazepine, phenobarbital) are expected to decrease the absorption of tenofovir alafenamide, resulting in decreased plasma concentration of tenofovir alafenamide, which may lead to loss of therapeutic effect of Emtritaf 200/25 and development of resistance. Co-administration of Emtritaf 200/25 with other medicines that inhibit P-gp and BCRP activity (e.g., cobicistat, ritonavir, ciclosporin) is expected to increase the absorption and plasma concentration of tenofovir alafenamide. Based on data from an in vitro study, co-administration of tenofovir alafenamide and xanthine oxidase inhibitors (e.g., febuxostat) is not expected to increase systemic exposure to tenofovir in vivo. Tenofovir alafenamide is not an inhibitor of CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, or CYP2D6 in vitro. It is not an inhibitor or inducer of CYP3A in vivo. Tenofovir alafenamide is a substrate of OATP1B1 and OATP1B3 in vitro. The distribution of tenofovir alafenamide in the body may be affected by the activity of OATP1B1 and OATP1B3.

Other interactions: Tenofovir alafenamide is not an inhibitor of human uridine diphosphate glucuronosyltransferase (UGT) 1A1 in vitro. It is not known whether tenofovir alafenamide is an inhibitor of other UGT enzymes. Emtricitabine did not inhibit the glucuronidation reaction of a non-specific UGT substrate in vitro. Interactions between the components of Emtritaf 200/25 and potential co-administered medicines are listed in Table 2 (increase is indicated as u201cu2191u201d, decrease as u201cu2193u201d, no change as u201cu2194 u201d). The interactions described are based on studies conducted with the components of Emtritaf 200/25 as individual agents and/or in combination, or are potential drug-drug interactions that may occur with Emtritaf 200/25.

Table 2: Interactions between the individual components of Emtritaf 200/25 and other medicines

Medicine by therapeutic areas 1 Effects on medicine levels. Mean percent change in AUC, C max , C min 2 Recommendation concerning co-administration with Emtritaf 200/25

ANTI-INFECTIVES

Antifungals

Ketoconazole

Itraconazole

Interaction not studied with either of the components of Emtritaf 200/25. Co-administration of ketoconazole or itraconazole, which are potent P-gp inhibitors, is expected to increase plasma concentrations of tenofovir alafenamide. The recommended dose of Emtritaf 200/25 is 200/10 mg once daily.

Fluconazole

Isavuconazole

Interaction not studied with either of the components of Emtritaf 200/25. Co-administration of fluconazole or isavuconazole may increase plasma concentrations of tenofovir alafenamide. Dose Emtritaf 200/25 according to the concomitant antiretroviral (see section 4.2).

Antimicrobials

Rifabutin

Rifampicin

Rifapentine

Interaction not studied with either of the components of Emtritaf 200/25. Co-administration of rifampicin, rifabutin, and rifapentine, all of which are P-gp inducers, may decrease tenofovir alafenamide plasma concentrations, which may result in loss of therapeutic effect and development of resistance. Co-administration of Emtritaf 200/25 and rifabutin rifampicin, or rifapentine is not recommended.

Anti-hepatitis C virus medicines

Ledipasvir (90 mg once daily)/ sofosbuvir (400 mg once daily), emtricitabine (200 mg once daily)/ tenofovir alafenamide (10 mg once daily)

Ledipasvir: AUC: u2191 79 % Cmax: u2191 65 % Cmin: u2191 93 % Sofosbuvir: AUC: u2191 47 % No dose adjustment of ledipasvir or sofosbuvir is required. Dose Emtritaf 200/25 according to the concomitant antiretroviral (see section 4.2).

Women of childbearing potential/contraception in males and females: The use of Emtritaf 200/25 should be accompanied by the use of effective contraception.

Pregnancy: The use of Emtritaf 200/25 is not recommended in pregnancy unless no other appropriate medicine that is known to be safe in pregnancy is available, not tolerated or has failed. Data on pregnant women (more than 1,000 exposed outcomes) indicate no malformative nor foetal/neonatal toxicity associated with emtricitabine. Animal studies do not indicate direct or indirect harmful effects of emtricitabine with respect to fertility parameters, pregnancy, foetal development, parturition or postnatal development. There are no or limited data (less than 300 pregnancy outcomes) from the use of tenofovir alafenamide in pregnant women. Studies of tenofovir alafenamide in animals have shown no evidence of harmful effects on fertility parameters, pregnancy, or foetal development. Nucleos(t)ide analogues, as in Emtritaf 200/25, may impact on mitochondrial function to a variable degree. There have been reports of mitochondrial dysfunction in HIV negative infants exposed in utero and/or postnatally to nucleoside analogues. The main adverse reactions reported are haematological disorders (anaemia, neutropenia), peripheral neuropathy and metabolic disorders (hyperlactataemia, hyperlipasaemia). These events have often been transitory. Late onset neurological disorders have been reported (hypertonia, convulsion, abnormal behaviour). Whether such neurological disorders are transient or permanent is unknown. These findings should be considered and investigated for any baby/ infant/child exposed in utero to nucleos(t)ide analogues, who present with severe clinical findings of unknown aetiology, particularly neurologic findings.

Breastfeeding: Emtritaf 200/25 should not be used by women breast-feeding their babies as possible harm to their babies cannot be excluded. Emtricitabine is excreted in human milk. In animal studies it has been shown that tenofovir is excreted in milk. In order to avoid transmission of HIV to the infant it is recommended that HIV infected women do not breast-feed their infants under any circumstances.

Fertility: There are no data on fertility from the use of Emtritaf 200/25 in humans. In animal studies there were no effects of emtricitabine and tenofovir alafenamide on mating or fertility parameters.

Emtritaf 200/25 may affect the ability to drive and use machines. Patients should not drive and use machines until they know how treatment with Emtritaf 200/25 affects them. Patients should be informed that dizziness and fatigue have been reported during treatment with Emtricitabine & Tenofovir Alafenamide Fumarate as in Emtritaf 200/25.

Summary of the safety profile: The most frequently reported adverse drug reactions, during controlled clinical trials with emtrictabine and tenofovir alafenamide were diarrhoea, nausea and headache.

Tabulated summary of adverse reactions

System organ class Frequent Less frequent Frequency unknown

Blood and lymphatic system anaemia

Psychiatric disorders Abnormal dreams

Nervous system disorders Headache, dizziness

Gastrointestinal disorders Nausea, diarrhoea, vomiting, abdominal pain, flatulence dyspepsia

Skin and subcutaneous tissue disorders Rash Angioedema, urticaria

Musculoskeletal and connective tissue disorders Arthralgia

General disorders and administration site conditions Fatigue

Reporting of suspected adverse reactions: Reporting suspected adverse reactions after authorisation of the medicine is important. It allows continued monitoring of the benefit/risk balance of the medicine. Health care providers are asked to report any suspected adverse reactions to SAHPRA via the Med Safety APP (Medsafety X SAHPRA) and eReporting platform (who-umc.org) found on SAHPRA website or to Macleods Pharmaceuticals SA (Pty) Ltd. at [email protected].

In overdose, side effects can be precipitated and/or be of increased severity. If overdose occurs the patient must be monitored for evidence of toxicity (see section 4.8). Treatment of overdose with Emtritaf 200/25 consists of general symptomatic and supportive measures including monitoring of vital signs as well as observation of the clinical status of the patient. Emtricitabine can be removed by haemodialysis, which removes approximately 30 % of the emtricitabine dose over a 3hour dialysis period starting within 1,5 hours of emtricitabine dosing. Tenofovir is efficiently removed by haemodialysis with an extraction coefficient of approximately 54 %. It is not known whether emtricitabine or tenofovir can be removed by peritoneal dialysis.