Atebiva 200mg/25 mg Tablets

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

Table 1: Dose of ATEBIVA according to third agent in the HIV treatment regimen

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

Elderly

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

Renal impairment

No dose adjustment of ATEBIVA 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. ATEBIVA 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 ATEBIVA is required in adults with end stage renal disease (estimated CrCl < 15 mL/min) on chronic haemodialysis; however, ATEBIVA should generally be avoided but may be used in these patients (see sections 4.4 and 5.2). On days of haemodialysis, ATEBIVA should be administered after completion of haemodialysis treatment.

Hepatic impairment

No dose adjustment of ATEBIVA is required in patients with mild to moderate hepatic impairment. ATEBIVA has not been studied in patients with severe hepatic impairment (Child-Pugh Class C); therefore, ATEBIVA 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 ATEBIVA in children younger than 12 years of age, or weighing < 35 kg, have not been established. No data are available.

Method of administration

ATEBIVA 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 substances 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 ATEBIVA 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 ATEBIVA 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 ATEBIVA 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.

Use of ATEBIVA can result in hepatomegaly due to non-alcoholic fatty liver disease (hepatic steatosis).

The safety and efficacy of ATEBIVA 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 new-born/infant/child exposed in utero to nucleos(t)ide analogues, including HIV negative infants/children who present with severe clinical findings of unknown etiology, 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 analogs, including emtricitabine, a component of ATEBIVA, and tenofovir DF, another prodrug of tenofovir, alone or in combination with other antiretrovirals. Treatment with ATEBIVA 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 ATEBIVA 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

ATEBIVA 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 ATEBIVA is administered with a third nucleoside analogue.

Opportunistic infections

Patients receiving ATEBIVA 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.

The co-administration of ATEBIVA 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). ATEBIVA should not be administered concomitantly with medicines containing tenofovir alafenamide, tenofovir disoproxil, emtricitabine, lamivudine or adefovir dipivoxil.

Women of childbearing potential / contraception in males and females

The use of ATEBIVA should be accompanied by the use of effective contraception.

Pregnancy

The use of ATEBIVA 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 (see section 5.3).

Nucleos(t)ide analogues, as in ATEBIVA, 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 etiology, particularly neurologic findings.

Breast-feeding

ATEBIVA 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 ATEBIVA in humans. In animal studies there were no effects of emtricitabine and tenofovir alafenamide on mating or fertility parameters (see section 5.3).

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

Summary of the safety profile

Assessment of adverse reactions is based on safety data from across all Phase 2 and 3 studies in which 3,112 HIV-1 infected patients received medicines containing emtricitabine and tenofovir alafenamide and from post-marketing experience. In clinical studies of 866 treatment-nau00efve adult patients receiving emtricitabine and tenofovir alafenamide with elvitegravir and cobicistat as the fixed-dose combination tablet elvitegravir 150 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir alafenamide (as fumarate) 10 mg (E/C/F/TAF) through 144 weeks, the most frequently reported adverse reactions were diarrhoea (7 %), nausea (11 %), and headache (6 %).

Tabulated summary of adverse reactions

The adverse reactions in Table 3 are listed by system organ class and frequency. Frequencies are defined as follows: very common (u2265 1/10) common (u2265 1/100 to < 1/10) and uncommon (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

Uncommon: Anaemia

Psychiatric disorders

Common: abnormal dreams

Nervous system disorders

Common: headache, dizziness

Gastrointestinal disorders

Very common: nausea

Common: diarrhoea, vomiting, abdominal pain, flatulence

Uncommon: dyspepsia

Skin and subcutaneous tissue disorders

Common: Rash

Musculoskeletal and connective tissue disorders

Uncommon: arthralgia

General disorders and administration site conditions

Common: 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 ATEBIVA while maintaining the third antiretroviral agent, increases from baseline were observed in the fasting lipid parameters total cholesterol, direct LDL cholesterol and triglycerides in the ATEBIVA arm. None of the changes was considered clinically relevant.

Metabolic parameters

Weight and levels of blood lipids and glucose may increase during ATEBIVA 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).

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of ATEBIVA is important. It allows continued monitoring of the benefit/risk balance of the medicine. Healthcare providers are asked to report any suspected adverse reactions to SAHPRA via the u201c6.04 Adverse Drug Reactions Reporting Formu201d found online under SAHPRAu2019s publications: https://www.sahpra.org.za/Publications/Index/8.

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 ATEBIVA 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 3-hour 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.