Vironeto 300 mg Tablet

HIV-1 infection
VIRONETO is indicated in combination with other antiretroviral medicines for the treatment of HIV-1 infection. This indication is based on analyses of plasma HIV-1 RNA levels and CD4 cell counts in controlled studies of VIRONETO in treatment-nau00efve adults and in treatment-experienced adults.

Chronic Hepatitis B
VIRONETO is indicated as monotherapy in HIV uninfected patients for the treatment of chronic hepatitis B in adults 18 years of age and older with compensated liver disease, with evidence of active viral replication, persistent elevated ALT and histological evidence of active inflammation and/or fibrosis. The following should be considered when initiating therapy with VIRONETO for the treatment of HBV infection:

• The indication in adults is based on safety and efficacy data from treatment of subjects who were nucleoside-treatment-nau00efve and subjects who were treatment-experienced with documented resistance to lamivudine. Subjects were adults with HBeAg-positive and HBeAg-negative chronic hepatitis B with compensated liver disease.

Posology
Adults: For the treatment of HIV-1 or chronic hepatitis B in adults: The dose of VIRONETO (tenofovir disoproxil fumarate) is 300 mg once daily taken orally, without regard to food. Chronic Hepatitis B Safety and efficacy of VIRONETO in patients younger than 18 years of age have not been established. Significantly increased medicine exposure occurred when VIRONETO was administered to patients with moderate to severe renal impairment (see section 4.3). It is recommended that estimated creatinine clearance be assessed in all patients prior to initiating therapy and as clinically appropriate during therapy with VIRONETO. In patients at risk of renal dysfunction, including patients who have previously experienced renal events while receiving adefovir dipivoxil, it is recommended that estimated creatinine clearance, serum phosphorus, urine glucose, and urine protein be assessed prior to initiation of VIRONETO, and periodically during VIRONETO therapy. Routine monitoring of estimated creatinine clearance, serum phosphorus, urine glucose, and urine protein should be performed in patients with mild renal impairment (see section 4.4).

Method of administration
Oral use. VIRONETO may be taken with or without food.

VIRONETO is contraindicated in:

• Patients with known hypersensitivity to tenofovir disoproxil fumarate or to any of the excipients of VIRONETO (see section 6.1).
• Pregnancy and lactation (see section 4.6).
• VIRONETO should not be used in combination with the fixed-dose combination medicines containing emtricitabine 200 mg and tenofovir disoproxil fumarate 300 mg, or other fixed dose combination medicines that contain tenofovir DF, since it is an ingredient of these medicines.

Patients to be treated with VIRONETO for hepatitis B infection should be proven to be negative for HIV infection and should be tested regularly for HIV infection. There are no study results demonstrating the effect of VIRONETO on clinical progression of HIV-1.

Lactic acidosis/severe hepatomegaly with steatosis
Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, has been reported with the use of nucleoside analogues such as VIRONETO alone, or in combination with other antiretrovirals. A majority of these cases have been in women. Obesity and prolonged nucleoside exposure may be risk factors. Particular caution should be exercised when administering nucleoside analogues such as VIRONETO to any patient with known risk factors for liver disease. However, cases have also been reported in patients with no known risk factors. Treatment with VIRONETO should be suspended in any patient 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).

Lactic acidosis/hyperlactataemia
Use of VIRONETO can result in potentially fatal lactic acidosis as a consequence of mitochondrial dysfunction. Clinical features 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 < 2 mmol/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 lactate has settled, use medicines that are less likely to cause lactic acidosis. Exclude other causes (e.g. sepsis, uraemia, diabetic ketoacidosis, thyrotoxicosis and hyperthyroidism).
• Lactate > 10 mmol/L: STOP all therapy (80 % mortality).

The above lactate values may not be applicable to paediatric patients. Caution should be exercised when administering VIRONETO to patients with known risk factors for liver disease. Treatment with VIRONETO should be suspended in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or hepatotoxicity.

Patients with moderate to severe renal impairment
In patients with moderate to severe renal impairment, the terminal half-life of VIRONETO is increased due to decreased clearance. The dose of VIRONETO should therefore be adjusted (see section 4.2). VIRONETO is principally eliminated by the kidney. Renal impairment, including cases of acute renal failure and Fanconi syndrome (renal tubular injury with severe hypophosphatemia), has been reported in association with the use of VIRONETO (see sections 4.3 and 4.8). It is recommended that creatinine clearance be calculated in all patients prior to initiating therapy, and as clinically appropriate, during therapy with VIRONETO. Routine monitoring of calculated creatinine clearance and serum phosphorus should be performed in patients at risk for renal impairment (see section 4.3).

Bone effects
Persistent or worsening bone pain, pain in extremities, fractures and/or muscular pain or weakness may be manifestations of proximal renal tubulopathy and should prompt an evaluation of renal function in at-risk patients. These manifest as bone pain or pain in extremities and which may contribute to fractures, have been reported in association with the use of VIRONETO (see section 4.8). Arthralgias and muscle pain or weakness have also been reported in cases of proximal renal tubulopathy. Hypophosphatemia and osteomalacia secondary to proximal renal tubulopathy should be considered in patients at risk of renal dysfunction who present with persistent or worsening bone or muscle symptoms while receiving medicines containing tenofovir DF (see section 4.4). Bone monitoring should be considered for HIV infected patients who have a history of pathologic bone fracture or are at risk for osteopenia. Although the effect of supplementation with calcium and vitamin D was not studied, such supplementation may be beneficial for all patients. If bone abnormalities are suspected, then appropriate consultation should be obtained.

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 combination antiretroviral therapy (CART), including components of VIRONETO. Patients should be advised to seek medical advice if they experience joint aches and pain, joint stiffness or difficulty in movement.

Patients with HIV and hepatitis B or C virus co-infection
Patients with chronic hepatitis B or C and treated with antiretroviral therapy are at an increased risk for severe and potentially fatal hepatic adverse reactions. Medical practitioners should refer to current HIV treatment guidelines for the optimal management of HIV infection in patients co-infected with hepatitis B virus (HBV). In case of concomitant antiviral therapy for hepatitis B or C, please refer also to the relevant professional information for these medicines. Patients co-infected with HIV and HBV who discontinue VIRONETO should be closely monitored with both clinical and laboratory follow-up 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. Only relevant to lamivudine, tenofovir and emtricitabine (FTC): Discontinuation of VIRONETO therapy in patients co-infected with HIV and HBV may be associated with severe, acute exacerbations of hepatitis.

Lipodystrophy and metabolic abnormalities
Combination antiretroviral therapy has been associated with the redistribution/accumulation of body fat, including central obesity, dorso-cervical fat, enlargement (buffalo hump), peripheral wasting, facial wasting and breast enlargement, and elevated serum lipid and glucose levels in HIV patients. Clinical examination should include evaluation for physical signs of fat redistribution. Patients with evidence of lipodystrophy should have a thorough cardiovascular risk assessment.

Immune reconstitution inflammatory syndrome
Immune reconstitution inflammatory syndrome (IRIS) 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 Anti-Retroviral Therapy (cART). Typically, such reaction presents by paradoxical deterioration of opportunistic infections being treated or with unmasking of an asymptomatic opportunistic disease, often with an atypical inflammatory presentation. IRIS usually develops within the first three months of initiation of ART and occurs more commonly in patients with low CD4 counts. Common examples of IRIS reactions to opportunistic diseases are tuberculosis, cytomegalovirus retinitis, and cryptococcal meningitis. Appropriate treatment of the opportunistic disease 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 IRIS. Autoimmune disorders (such as Gravesu2019 disease) have also been reported as IRIS reactions; however, the reported time to onset is more variable and these events can occur many months after initiation of treatment.

Mitochondrial dysfunction
Nucleoside and nucleotide analogues have been demonstrated in vitro and in vivo to cause a variable degree of mitochondrial damage. There have been reports of mitochondrial dysfunction in HIV negative infants exposed in utero and/or postnatally to nucleoside analogues. Apart from lactic acidosis/hyperlactataemia (see above) other manifestations of mitochondrial dysfunction include haematological disorders (anaemia, neutropenia), and peripheral neuropathy. Some late-onset neurological disorders have been reported (hypertonia, convulsion, abnormal behaviour). It is not known whether the neurological disorders are transient or permanent. Any foetus exposed in utero to nucleoside and nucleotide analogues, even HIV negative infants/children, should have clinical and laboratory follow-up and should be fully investigated for possible mitochondrial dysfunction in case of relevant signs or symptoms.

Pancreatitis
Pancreatitis has been observed in some patients receiving tenofovir. Pancreatitis must be considered whenever a patient develops abdominal pain, nausea, vomiting or elevated biochemical markers. Discontinue use of VIRONETO until diagnosis of pancreatitis is excluded.

Liver disease
Use of VIRONETO can result in hepatomegaly due to non-alcoholic fatty liver disease (hepatic steatosis). The safety and efficacy of VIRONETO 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 relevant package inserts for 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, interruption or discontinuation of treatment must be considered.

Opportunistic infections
Patients receiving VIRONETO may continue to develop opportunistic infections and other complications of HIV infection, and therefore should remain under close clinical observation by healthcare professionals experienced in the treatment of patients with HIV associated diseases. Regular monitoring of viral load and CD4 counts needs to be done.

The risk of HIV transmission to others
Patients must be advised that treatment with Vironeto, has not been proven to prevent the risk of transmission of HIV to others through sexual contact or blood contamination. Appropriate precautions should continue to be employed.

Excipients
VIRONETO contains lactose monohydrate. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take VIRONETO.

Use in the elderly
Clinical studies did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. In general, dose selection for the elderly patient should be done with caution, keeping in mind the greater frequency of decreased hepatic, renal or cardiac function, and of concomitant disease or other medicine therapy.

Paediatric population
Safety and effectiveness in paediatric patients and patients < 18 years of age (or less than 35 kg) have not been established.

At concentrations substantially higher (~300-fold) than those observed in vivo, tenofovir did not inhibit in vitro medicine metabolism mediated by any of the following human CYP450 isoforms: CYP3A4, CYP2D6, CYP2C9 or CYP2E1. However, a small (6 %) but statistically significant reduction in metabolism of CYP1A substrate was observed. Based on the results of in vitro experiments and the known elimination pathway of tenofovir, the potential for CYP450 mediated interactions involving tenofovir with other medicines is low.

Tenofovir, as in VIRONETO, is primarily excreted by the kidneys by a combination of glomerular filtration and active tubular secretion. Co-administration VIRONETO with medicines that are eliminated by active tubular secretion may increase serum concentrations of either tenofovir or the co-administered medicines due to competition for this elimination pathway. Medicines that decrease renal function may also increase serum concentrations of tenofovir.

VIRONETO has been evaluated in healthy volunteers in combination with abacavir, adefovir dipivoxil, atazanavir, didanosine, efavirenz, emtricitabine, indinavir, lamivudine, lopinavir/ritonavir, methadone, nelfinavir, oral contraceptives, ribavirin and saquinavir/ritonavir. Tables 1 and 2 summarise pharmacokinetic effects of co-administered medicine on VIRONETO pharmacokinetics and effects of VIRONETO on the pharmacokinetics of co-administered medicines. Table 3 summarises the medicine interaction between VIRONETO and didanosine. When administered with multiple doses of VIRONETO, the C max and AUC of didanosine 400 mg increased significantly. The mechanism of this interaction is unknown. When didanosine 250 mg enteric coated capsules were administered with tenofovir, systemic exposures to didanosine were similar to those seen with the 400 mg enteric-coated capsules alone under fasted conditions.

The safety of VIRONETO in pregnancy and lactation has not been established (see section 4.3).

Pregnancy
There are no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, VIRONETO should not be used during pregnancy (see section 4.3).

Breastfeeding
Nursing Mothers: HIV-infected mothers should not breastfeed their infants, to avoid risking postnatal transmission of HIV. Samples of breast milk obtained from five HIV-1 infected mothers in the first post-partum week show that tenofovir is secreted in human milk. The impact of this exposure in breastfed infants is unknown. Because of both the potential for HIV transmission and the potential for serious adverse reactions in nursing infants, mothers should be instructed not to breastfeed if they are receiving VIRONETO (see section 4.3).

Fertility
There is no information on fertility with VIRONETO.

Since adverse reactions such as dizziness have been reported in patients receiving tenofovir, patients should not drive, use machinery or perform any tasks that require concentration, until they are certain that VIRONETO does not adversely affect their ability to do so (see section 4.8).

a. Summary of the safety profile
HIV-1 and hepatitis B: In patients receiving tenofovir disoproxil, rare events of renal impairment, renal failure and proximal renal tubulopathy (including Fanconi syndrome) sometimes leading to bone abnormalities (infrequently contributing to fractures) have been reported. Monitoring of renal function is recommended for patients receiving tenofovir disoproxil (see section 4.4). HIV-1: Approximately one third of patients are expected to experience adverse reactions following treatment with tenofovir disoproxil in combination with other antiretroviral medicines. These reactions are usually mild to moderate gastrointestinal events. Approximately 1 % of tenofovir disoproxil-treated patients discontinued treatment due to the gastrointestinal events. Co-administration of tenofovir and didanosine is not recommended as this increases adverse reactions (see section 4.5). Less frequently, pancreatitis and lactic acidosis, sometimes fatal, have been reported (see section 4.4).

b. Tabulated summary of adverse reactions
The following adverse reactions were associated with tenofovir disoproxil based on clinical study and post-marketing experience.

1 This adverse reaction may occur as a consequence of proximal renal tubulopathy. It is not considered to be causally associated with tenofovir disoproxil in the absence of this condition.

2 This adverse reaction was identified through post-marketing surveillance

c. Description of selected adverse reactions
HIV-1 and hepatitis B
Renal impairment
As tenofovir disoproxil may cause renal damage, monitoring of renal function is recommended (see sections 4.4). Proximal renal tubulopathy generally resolved or improved after tenofovir disoproxil discontinuation. However, in some patients, declines in creatinine clearance did not completely resolve despite tenofovir disoproxil discontinuation. Patients at risk of renal impairment (such as patients with baseline renal risk factors, advanced HIV disease, or patients receiving concomitant nephrotoxic medications) are at increased risk of incomplete recovery of renal function despite tenofovir disoproxil discontinuation (see section 4.4).

HIV-1
Metabolic parameters
Weight and levels of blood lipids and glucose may increase during antiretroviral therapy (see section 4.4).

Immune reactivation syndrome
In HIV-infected patients with severe immune deficiency at the time of initiation of antiretroviral therapy, an inflammatory reaction to asymptomatic or residual opportunistic infections may arise. Autoimmune disorders (such as Gravesu2019 disease) have also been reported (see section 4.4).

Osteonecrosis
Cases of osteonecrosis have been reported. The frequency of this is unknown (see section 4.4).

Hepatitis B
Exacerbations of hepatitis during treatment
In studies with nucleoside-nau00efve patients, on-treatment ALT elevations > 10 times ULN (upper limit of normal) and > 2 times baseline occurred in 2,6 % of tenofovir disoproxil-treated patients. Most cases were associated with a u2265 2 log10 copies/ml reduction in viral load that preceded or coincided with the ALT elevation. Periodic monitoring of hepatic function is recommended during treatment (see section 4.4).

Exacerbations of hepatitis after discontinuation of treatment
In HBV-infected patients, clinical and laboratory evidence of exacerbations of hepatitis have occurred after discontinuation of HBV therapy (see section 4.4).

Paediatric population
HIV-1 therapy
The adverse reactions in paediatric patients who received tenofovir disoproxil were consistent with those in clinical studies of tenofovir disoproxil in adults. Reductions in bone mineral density (BMD) have been reported in paediatric patients. In HIV-infected adolescents, the BMD Z-scores in subjects who received tenofovir disoproxil were lower than those in subjects who received placebo. In HIV-infected children, the BMD Z-scores in subjects who switched to tenofovir disoproxil were lower than those in subjects who remained on regimens containing stavudine or zidovudine (see section 4.4). In one study, 4 out of 89 paediatric patients treated with tenofovir disoproxil (median tenofovir disoproxil treatment 312 weeks) discontinued due to adverse reactions consistent with proximal renal tubulopathy. Seven patients had estimated glomerular filtration rate (GFR) values between 70 and 90 ml/minute/1,73 m2. Among them, two patients had a clinically meaningful decline in estimated GFR which improved after discontinuation of tenofovir disoproxil.

Pre-exposure prophylaxis
Tenofovir is not indicated for PrEP in children. No safety data are available in adolescents.

Chronic hepatitis B
The adverse reactions in adolescent patients who received treatment with tenofovir disoproxil were consistent with those in clinical studies of tenofovir disoproxil in adults. Bone mineral density (BMD) declined in HBV infected adolescents. The BMD Z-scores in subjects who received tenofovir disoproxil were lower than those in subjects who received placebo (see section 4.4).

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 u201c6.04 Adverse Drug Reactions & Quality Problem Reporting Formu201d, found online under SAHPRAu2019s publications: https://sahpra.org.za/wp-content/uploads/2020/01/6.04_ARF1_v5.1_27Jan2020.pdf

Symptoms
Limited clinical experience at doses higher than the therapeutic dose of tenofovir 300 mg is available. In a study, 600 mg tenofovir was administered to 8 patients orally for 28 days. The effects of higher doses are not known.

Management
If overdose occurs the patient must be monitored for evidence of toxicity (see section 4.8), and standard supportive treatment applied as necessary. Tenofovir can be removed by haemodialysis; the median haemodialysis clearance of tenofovir is 134 ml/minute. It is not known whether tenofovir can be removed by peritoneal dialysis.