Aurotem 200mg & 25mg FC tablets

AUROTEM 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. AUROTEM should be administered as shown in Table 1.

Table 1: Dose of AUROTEM according to third medicine in the HIV treatment regimen.

Dose of AUROTEM Third medicine in HIV treatment regimen (see section 4.5) Emtricitabine/Tenofovir Alafenamide 200/10 mg Atazanavir with ritonavir or cobicistat Darunavir with ritonavir or cobicistat Lopinavir with ritonavir AUROTEM 200/25 mg once daily Dolutegravir, efavirenz, maraviroc, nevirapine, rilpivirine, raltegravir Emtricitabine/Tenofovir Alafenamide 200/10 mg in combination with darunavir 800 mg and cobicistat 150 mg, administered as a fixed-dose combination tablet, was studied in treatment-naive subjects.

If the patient misses a dose of AUROTEM within 18 hours of the time it is usually taken, the patient should take AUROTEM as soon as possible and resume the normal dosing schedule. If a patient misses a dose of AUROTEM 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 AUROTEM another tablet should be taken.

Special populations

Elderly No dose adjustment of AUROTEM is required in elderly patients (see sections 5.1 and 5.2).

Renal impairment No dose adjustment of AUROTEM 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. AUROTEM 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 AUROTEM is required in adults with end stage renal disease (estimated CrCl < 15 mL/min) on chronic haemodialysis; however, AUROTEM should generally be avoided but may be used in these patients (see sections 4.4 and 5.2). On days of haemodialysis, AUROTEM should be administered after completion of haemodialysis treatment. AUROTEM should be avoided in patients with estimated CrCl u2265 15 mL/min and < 30 mL/min as the safety of AUROTEM has not been established in this population. AUROTEM 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 AUROTEM is required in patients with mild to moderate hepatic impairment. AUROTEM has not been studied in patients with severe hepatic impairment (Child-Pugh Class C); therefore, AUROTEM 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 AUROTEM in children younger than 12 years of age, or weighing < 35 kg, have not been established. No data are available.

Method of administration For oral use. AUROTEM 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.

AUROTEM is contraindicated in patients with hypersensitivity to active substances or to any of the other excipients of AUROTEM (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 AUROTEM 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 AUROTEM 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 AUROTEM 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 AUROTEM can result in hepatomegaly due to non-alcoholic fatty liver disease (hepatic steatosis). The safety and efficacy of AUROTEM 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 life style. For lipids, there is in some cases evidence for a treatment effect, while for weight gain there is no strong evidence relating this to any particular treatment. For monitoring of blood lipids and glucose reference is made to established HIV treatment guidelines. Lipid disorders should be managed as clinically appropriate.

Mitochondrial dysfunction following exposure in utero Nucleos(t)ide analogues 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 AUROTEM, and tenofovir DF, another prodrug of tenofovir, alone or in combination with other antiretrovirals. Treatment with AUROTEM 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 AUROTEM 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 AUROTEM 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 AUROTEM is administered with a third nucleoside analogue.

Opportunistic infections Patients receiving AUROTEM 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. Patients with end stage renal disease on chronic haemodialysis AUROTEM 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).

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 AUROTEM and development of resistance. Co-administration of AUROTEM 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 AUROTEM and potential co-administered medicines are listed in Table 2 (increase is indicated as u201cu2191u201d, decrease as u201cu2193u201d, no change as u201cu2194u201d). The interactions described are based on studies conducted with AUROTEM, or the components of AUROTEM as individual medicines and/or in combination, or are potential medicine interactions that may occur with AUROTEM.

Women of childbearing potential/contraception in males and females The use of AUROTEM should be accompanied by the use of effective contraception.

Pregnancy The use of AUROTEM 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 AUROTEM, 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 AUROTEM should not be used by women breastfeeding 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 AUROTEM in humans. In animal studies there were no effects of emtricitabine and tenofovir alafenamide on mating or fertility parameters.

AUROTEM may affect the ability to drive and use machines. Patients should not drive and use machines until they know how treatment with AUROTEM affects them. Patients should be informed that dizziness and fatigue have been reported during treatment with AUROTEM.

Tabulated summary of adverse reactions The adverse reactions in Table 3 are listed by system organ class and frequency. Frequencies are defined as follows: frequent (u2265 1/10), (u2265 1/100 to < 1/10) and less frequent (u2265 1/1,000 to < 1/100)

Table 3: Tabulated list of adverse reactions reported in Clinical Trials

Frequency Adverse reaction Blood and lymphatic system disorders Less frequent: anaemia Psychiatric disorders Frequent: abnormal dreams Nervous system disorders Frequent: headache, dizziness Gastrointestinal disorders Frequent: nausea, diarrhoea, vomiting, abdominal pain, flatulence Less frequent: dyspepsia Skin and subcutaneous tissue disorders Frequent: Rash Musculoskeletal and connective tissue disorders Less frequent: arthralgia General disorders and administration site conditions Frequent: fatigue

1 All adverse reactions were identified from clinical studies of F/TAF containing products. The frequencies were derived from Phase 3 E/C/F/TAF clinical studies in 866 treatment-nau00efve adult patients through 144 weeks of treatment (GS-US-292-0104 and GS-US-292-0111).

2 This adverse reaction was not observed in the clinical studies of F/TAF-containing products but identified from clinical studies or post-marketing experience for emtricitabine when used with other antiretrovirals.

Table 4: Tabulated list of Post marketing reported side effects Adverse reaction

Blood and lymphatic system disorders Anaemia Skin and subcutaneous tissue disorders Angioedema, urticaria

1 This adverse reaction was not observed in the clinical studies of F/TAF-containing products but identified from clinical studies or post-marketing experience for emtricitabine when used with other antiretrovirals.

2 This adverse reaction was identified through post-marketing surveillance for emtricitabine-containing products.

3 This adverse reaction was identified through post-marketing surveillance for tenofovir alafenamide-containing products

Description of selected adverse reactions Changes in lipid laboratory tests In studies in treatment-nau00efve patients, increases from baseline were observed for the fasting lipid parameters total cholesterol, direct low-density lipoprotein (LDL)- and high-density lipoprotein (HDL)- cholesterol, and triglycerides at Week 144. The median (Q1, Q3) change from baseline in total cholesterol to HDL-cholesterol ratio at Week 144 was 0.2 (- 0,3, 0,7) in the E/C/F/TAF group. In a study of virologically suppressed patients switching from emtricitabine/tenofovir disoproxil fumarate to a fixed dose combination product while maintaining the third antiretroviral medicine, increases from baseline were observed in the fasting lipid parameters total cholesterol, direct LDL cholesterol and triglycerides in a fixed dose combination product arm. None of the changes was considered clinically relevant.

Metabolic parameters Weight and levels of blood lipids and glucose may increase during AUROTEM therapy. Paediatric population The safety of emtricitabine and tenofovir alafenamide was evaluated through 48 weeks in an open-label clinical study in which HIV-1 infected, treatment-nau00efve paediatric patients aged 12 to < 18 years received emtricitabine and tenofovir alafenamide in combination with elvitegravir and cobicistat as a fixed-dose combination tablet. The safety profile of emtricitabine and tenofovir alafenamide given with elvitegravir and cobicistat in 50 adolescent patients was similar to that in adults (see section 5.1).

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 AUROTEM 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.