Tavirant 200, 25, 25 mg Tablet

TAVIRANT is indicated in combination with other antiretroviral medicines for the treatment of adults infected with human immunodeficiency virus type 1 (HIV-1) (see sections 4.2 and 5.1).

Posology
Adults, weighing at least 35 kg. The recommended dose is one TAVIRANT tablet once a day with food.
Special Populations
Elderly patients
No dose adjustment of TAVIRANT is required in elderly patients.
Paediatric population
The safety and efficacy of TAVIRANT in children younger than 12 years of age, or weighing < 35 kg, have not been established. No data is available.
Renal impairment
No dose adjustment of TAVIRANT 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. TAVIRANT 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 TAVIRANT is required in adults with end stage renal disease (estimated CrCl < 15 mL/min) on chronic haemodialysis; however, TAVIRANT should generally be avoided but may be used in these patients (see sections 4.4 and 5.2). On days of haemodialysis, TAVIRANT should be administered after completion of haemodialysis treatment. TAVIRANT should be avoided in patients with estimated CrCl u2265 15 mL/min and < 30 mL/min as the safety of TAVIRANT has not been established in this population. TAVIRANT 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 dosage adjustment of TAVIRANT is required in patients with mild to moderate hepatic impairment (Child-Pugh score A or B). TAVIRANT has not been studied in patients with severe hepatic impairment (Child-Pugh Class C); therefore, TAVIRANT is not recommended for use in patients with severe hepatic impairment as no dose recommendations can be made (see sections 4.4).
Method of administration
TAVIRANT should be taken orally with food. 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.
• TAVIRANT should not be co-administered with medicines that can result in significant decreases in rilpivirine plasma concentrations (due to cytochrome P450 [CYP]3A enzyme induction or gastric pH increase), which may result in loss of therapeutic effect of TAVIRANT (see section 4.5), including:
• Carbamazepine, oxcarbazepine, phenobarbital, phenytoin, rifabutin, rifampicin, rifapentine.
• Omeprazole, esomeprazole, dexlansoprazole, lansoprazole, pantoprazole, rabeprazole.
• Dexamethasone (oral and parenteral doses), except as a single dose treatment.
• St. John's wort (Hypericum perforatum).

• Patients should be advised that current antiretroviral therapy does not cure HIV and has not been proven to prevent the transmission of HIV to others through blood, other bodily secretion or sexual contact. Appropriate precautions to prevent transmission of HIV should continue to be employed.
• Virologic Failure and Development of Resistance: There is insufficient data to justify the use in patients with prior NNRTI failure. Resistance testing and/or historical resistance data should guide the use of TAVIRANT (see section 5.1).
• Interaction with other medicines: Caution should be given to prescribing TAVIRANT with other medicines that may reduce the exposure of rilpivirine (see section 4.5). There is limited information available on the potential for a pharmacodynamic interaction between rilpivirine and medicines that prolong the QTc interval of the electrocardiogram. In a study of healthy subjects, supratherapeutic doses of rilpivirine (75 mg daily and 300 mg daily) have been shown to prolong the QTc interval of the electrocardiogram (see section 5.1 and 4.5). TAVIRANT should be used with caution when co-administered with medicines with a known risk of Torsade de Pointes.
• Co-administration of other medicines: The co-administration of TAVIRANT is not recommended with certain anticonvulsants (e.g., carbamazepine, oxcarbazepine, phenobarbitone and phenytoin), antimycobacterials (e.g., rifampicin, rifabutin, rifapentine), boceprevir, St. John's wort and HIV protease inhibitors other than atazanavir, lopinavir and darunavir (see section 4.5). TAVIRANT should not be administered concomitantly with medicines containing tenofovir alafenamide, tenofovir disoproxil, emtricitabine, lamivudine or adefovir dipivoxil.
• Fat distribution: Redistribution/accumulation of body fat, including central obesity, dorsocervical fat enlargement (buffalo lump), peripheral wasting, facial wasting, breast enlargement, cushingoid appearance and elevated serum lipid and glucose levels have been observed in HIV patients and those receiving antiretroviral therapy. The mechanism and long-term consequences of these events are currently unknown. A causal relationship has not been established.
• Immune reconstitution 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 Graves' 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 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 TAVIRANT 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 TAVIRANT 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 TAVIRANT 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 TAVIRANT can result in hepatomegaly due to non-alcoholic fatty liver disease (hepatic steatosis). The safety and efficacy of TAVIRANT 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 analogs, including emtricitabine, a component of TAVIRANT, and tenofovir disoproxil fumarate, another prodrug of tenofovir, alone or in combination with other antiretrovirals. Treatment with TAVIRANT 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 to 5 mmol/L with minimum symptoms: switch to medicines that are less likely to cause lactic acidosis.
  - Lactate 5 to 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 > 10 mmol/L: STOP all therapy (80 % mortality). The above values may not be applicable to paediatric patients. Caution should be exercised when administering TAVIRANT to patients with known risk factors for liver disease.
• Patients with HIV-1 harbouring mutations: TAVIRANT 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 TAVIRANT is administered with a third nucleoside analogue.
• Opportunistic infections: Patients receiving TAVIRANT 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: TAVIRANT should generally be avoided but may be used in adults with end stage renal disease (estimated CrCI < 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 CrCI < 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).
• Anhydrous lactose and lactose monohydrate: TAVIRANT contains anhydrous lactose and lactose monohydrate. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicine.

Interaction studies have only been performed in adults.
Emtricitabine and Tenofovir alafenamide
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 TAVIRANT and development of resistance. Co-administration of TAVIRANT 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, CYP286, 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 OATP183 in vitro. The distribution of tenofovir alafenamide in the body may be affected by the activity of OATP181 and OATP183.
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 emtricitabine and tenofovir alafenamide and potential co-administered medicines are listed in Table 1 (increase is indicated as u2191, decrease as u2193 and no change as u2194). The interactions described are based on studies conducted with emtricitabine and tenofovir alafenamide components of TAVIRANT as individual medicines and/or in combination or are potential drug-drug interactions that may occur with TAVIRANT.

Women of childbearing potential/ contraception in males and females
The use of TAVIRANT should be accompanied by the use of effective contraception.
Pregnancy
Safe use during pregnancy and lactation has not been established. The use of TAVIRANT containing emtricitabine and tenofovir alafenamide is not recommended in pregnancy. Data on pregnant women (more than 1,000 exposed outcomes) indicate no malformities 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 TAVIRANT, 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
Mothers should not breastfeed their infants when taking TAVIRANT. Emtricitabine is excreted in human milk. In animal studies it has been shown that tenofovir is excreted in milk. It is not known whether rilpivirine is secreted in human milk.
Fertility
There are no data on fertility from the use of TAVIRANT in humans. In animal studies there were no effects of emtricitabine and tenofovir alafenamide on mating or fertility parameters.

TAVIRANT may influence the ability to drive and use machines. Patients should not drive and use machines until they know how treatment with TAVIRANT affects them. Dizziness and somnolence may occur.

a) Summary of the safety profile
Emtricitabine and tenofovir alafenamide The most frequently reported adverse reactions in clinical studies of treatment-nau00efve patients taking emtricitabine +tenofovir alafenamide in combination with elvitegravir + cobicistat were nausea (11 %), diarrhoea (7 %), and headache (6 %). The most frequently reported adverse reactions in clinical studies of treatment-nau00efve patients taking rilpivirine hydrochloride in combination with emtricitabine + tenofovir disoproxil fumarate were nausea (9 %), dizziness (8 %), abnormal dreams (8 %), headache (6 %), diarrhoea (5 %) and insomnia (5 %).
b) Tabulated (or structured listing) summary of adverse reactions for emtricitabine and tenofovir alafenamide
Tabulated summary of adverse reactions The adverse reactions in Table 4 are listed by system organ class and highest frequency observed. Frequencies are defined as follows: very common (u2265 1/10), common (u2265 1/100 to < 1/10), uncommon (u2265 1/1,000 to < 1/100) or not known (cannot be estimated from the available data).
Emtricitabine and tenofovir alafenamide
Table 4: Tabulated list of adverse reactions
Frequency Adverse reaction
Blood and lymphatic system disorders Uncommon: Anaemia.
Psychiatric disorders Common: Abnormal dreams.
Nervous system disorders Very common: Headache, dizziness.
Gastrointestinal disorders Very common: Nausea, diarrhoea, vomiting, flatulence, upper abdominal pain. Uncommon: Dyspepsia.
Skin and subcutaneous tissue disorders Common: Rash.
Musculoskeletal and connective tissue disorders Uncommon: Arthralgia.
General disorders and administration site conditions Common: Fatigue.
Rilpivirine
Table 4: Tabulated list of adverse reactions
Frequency Adverse reaction
Blood and lymphatic system disorders Common: Increased AST, increased pancreatic amylase. Uncommon: Decreased haemoglobin, decreased platelet count, decreased white blood cell count, increased ALT, increased bilirubin, increased lipase, increased total cholesterol (fasted), increased LDL cholesterol (fasted), increased triglycerides (fasted). Not known: Increased creatinine.
Metabolism and nutrition disorders Uncommon: Decreased appetite.
Psychiatric Disorders Common: Depression, insomnia. Uncommon: Abnormal dreams, sleep disorders, depressed mood.
Nervous system disorders Common: Headache. Uncommon: Dizziness, somnolence.
Gastrointestinal disorders Uncommon: Abdominal pain, nausea, vomiting, abdominal discomfort.
Skin and subcutaneous tissue disorders Common: Rash.
General disorders and administration site conditions Uncommon: Fatigue.
Investigations Common: Transaminases increased.

In overdose, side effects can be precipitated and/or be of increased severity. There is no specific treatment for an overdose of TAVIRANT. If overdose occurs, the patient should be treated supportively with appropriate monitoring as necessary such as monitoring of vital signs and ECG (QT interval) as well as observation of the clinical status of the patient. Rilpivirine is highly bound to plasma proteins, it is unlikely that it will significantly be removed by dialysis. If indicated, elimination of unabsorbed rilpivirine may be achieved by gastric lavage. Administration of activated charcoal may also be used to aid in removal of unabsorbed rilpivirine. 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.