Viread 300mg Tablet

VIREAD is indicated in adults and adolescents for:

• HIV-1 infection
  VIREAD is indicated in combination with other antiretroviral medicines for the treatment of HIV-1 infection in adults and in adolescent patients u2265 12 years of age weighing u2265 35 kg. This indication is based on analyses of plasma HIV-1 RNA levels and CD4 cell counts in controlled studies of VIREAD in treatment-nau00efve adults and in treatment-experienced adults.
• Chronic Hepatitis B
  VIREAD is indicated as monotherapy in HIV uninfected patients for the treatment of chronic hepatitis B in adults and in adolescent patients u2265 12 years of age weighing u2265 35 kg 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 VIREAD 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 VIREAD (tenofovir disoproxil fumarate) is 300 mg once daily taken orally, without regard to food.

Adolescents 12 to 18 years of age
HIV-1 Infection and chronic hepatitis B (u2265 12 Years of Age and u2265 35 kg). Take one 300 mg VIREAD tablet (equivalent to tenofovir disoproxil 245 mg) once daily with or without food. In the treatment of chronic hepatitis B, the optimal duration of treatment is unknown.

Special populations

Renal impairment
Significantly increased medicine exposure occurred when VIREAD was administered to patients with moderate to severe renal impairment. It is recommended that estimated creatinine clearance be assessed in all patients prior to initiating therapy and as clinically appropriate during therapy with VIREAD. 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 VIREAD, and periodically during VIREAD 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).

Hepatic Impairment
Clinically relevant pharmacokinetic changes in patients with hepatic impairment are not observed. Therefore, no dose adjustment is required in patients with hepatic impairment.

Method of administration
For oral administration.

VIREAD is contraindicated in:

• Patients with hypersensitivity to tenofovir or to any excipients in VIREAD (see section 6.1).
• Pregnancy and lactation (see section 4.6).
• VIREAD 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 VIREAD 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 VIREAD on clinical progression of HIV-1.

General
VIREAD should not be co-administered with other medicines containing tenofovir disoproxil fumarate, or with medicines containing tenofovir alafenamide or adefovir dipivoxil.

Lactic Acidosis / Severe Hepatomegaly with Steatosis
Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues such as VIREAD 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 VIREAD 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 VIREAD 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 VIREAD 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 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 hyperlactataemia has resolved, 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).

Patients with moderate to severe renal impairment
In patients with moderate to severe renal impairment, the terminal half-life of VIREAD is increased due to decreased clearance. The dose of VIREAD should therefore be adjusted (see section 4.2).

VIREAD is principally eliminated by the kidney.
Renal insufficiency, elevated creatinine, renal impairment, including cases of acute renal failure and Fanconi syndrome (renal tubular injury with severe hypophosphataemia), has been reported in association with the use of VIREAD (see section 4.8).

Renal monitoring
It is recommended that creatinine clearance be calculated in all patients prior to initiating therapy, and as clinically appropriate, during therapy with VIREAD. Routine monitoring of calculated creatinine clearance and serum phosphorus should be performed in patients at risk for renal impairment, including patients who have previously experienced renal events while receiving adefovir dipivoxil.

Bone effects
There is limited clinical experience with VIREAD in paediatric patients. In clinical studies of HIV-1 infected patients and HBV infected patients 12 to <18 years of age, decreases in median BMD Z-scores were observed following treatment with VIREAD. 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.

In Study 903 through 144 weeks, decreases from baseline in bone mineral density (BMD) were seen at the lumbar spine and hip in both arms of the study. At week 144, there was a significantly greater mean percentage decrease from baseline in BMD at the lumbar spine in patients receiving VIREAD + lamivudine + efavirenz (-2,2 % u00b1 3,9) compared with patients receiving stavudine + lamivudine + efavirenz (-1,0 % u00b1 4,6). Changes in BMD at the hip were similar between the two treatment groups (-2,8 % u00b1 3,5 in the VIREAD group vs. -2,4 % u00b1 4,5 in the stavudine group). In both groups, the majority of the reduction in BMD occurred in the first 24 to 48 weeks of the study and this reduction was sustained through week 144. Twenty-eight percent of VIREAD-treated patients vs. 21 % of the stavudine-treated patients lost at least 5 % of BMD at the spine or 7 % of BMD at the hip. Clinically relevant fractures (excluding fingers and toes) were reported in four patients in the VIREAD group and six patients in the stavudine group. In addition, there were significant increases in biochemical markers of bone metabolism (serum bone-specific alkaline phosphatase, serum osteocalcin, serum C-telopeptide and urinary N-telopeptide) in the VIREAD group relative to the stavudine group, suggesting increased bone turnover. Serum parathyroid hormone levels and 1,25 Vitamin D levels were also higher in the VIREAD group. Except for bone-specific alkaline phosphatase, these changes resulted in values that remained within the normal range. The effects of VIREAD-associated changes in BMD and biochemical markers on long-term bone health and future fracture risk are unknown.

Cases of osteomalacia (associated with proximal renal tubulopathy) have been reported in association with the use of tenofovir. These manifest as bone pain or pain in extremities and which may contribute to fractures, have been reported in association with the use of VIREAD (see section 4.8). Arthralgias and muscle pain or weakness have also been reported in cases of proximal renal tubulopathy. Hypophosphataemia 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 and hepatitis B 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). 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
Due to the risk of development of HIV resistance, VIREAD should only be used as part of an appropriate antiretroviral combination regimen in HIV/HBV co-infected patients. 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 package inserts for these medicines. Patients co-infected with HIV and HBV who discontinue VIREAD 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 VIREAD 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, 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 and other generalised and/or focal mycobacterial infections, cytomegalovirus retinitis, cryptococcal meningitis, and Pneumocystis jiroveci pneumonia. 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 Graves' 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 post-natally 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 sign and symptoms.

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

Liver disease
Use of VIREAD can result in hepatomegaly due to non-alcoholic fatty liver disease (hepatic steatosis). The safety and efficacy of VIREAD 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, temporary or permanent discontinuation of treatment must be considered.

Opportunistic infections
Patients receiving VIREAD 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.

Excipients
VIREAD contains lactose which may have an effect on the glycaemic control of patients with diabetes mellitus. Patients with the rare hereditary conditions of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take VIREAD.

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 is low.

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

VIREAD has been evaluated in healthy volunteers in combination with abacavir, atazanavir, didanosine, efavirenz, emtricitabine, indinavir, lamivudine, lopinavir/ritonavir, ledipasvir/sofosbuvir, methadone, nelfinavir, oral contraceptives, ribavirin, saquinavir/ritonavir, sofosbuvir, sofosbuvir/velpatasvir, tacrolimus, tipranavir/ritonavir. No clinically significant interactions have been observed between VIREAD and efavirenz, methadone, nelfinavir, oral contraceptives, ribavirin or sofosbuvir.

Tables 2 and 3 summarise pharmacokinetic effects of co-administered medicine on VIREAD pharmacokinetics and effects of VIREAD on the pharmacokinetics of co-administered medicines.

Table 4 summarises the interaction between VIREAD and didanosine. When administered with multiple doses of VIREAD, 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 VIREAD, systemic exposures to didanosine were similar to those seen with the 400 mg enteric-coated capsules alone under fasted conditions.

VIREAD is contraindicated in pregnancy and lactation (see section 4.3).

Pregnancy
VIREAD should not be taken 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 at low levels estimated neonatal concentrations 128 to 266 times lower than the tenofovir IC 50. VIREAD-associated risks, including the risk of developing viral resistance to tenofovir, in infants breastfed by mothers being treated with VIREAD are 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 VIREAD (see section 4.3).

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

a) Tabulated list of adverse reactions

System organ class

• Frequent
• Less frequent
• Frequency unknown (cannot be estimated from the available data)

Immune system disorders
Allergic reaction (including angioedema)

Metabolism and nutrition disorders
Hypophosphataemia, lactic acidosis, hypokalemia

Nervous system disorders
Dizziness, insomnia

Respiratory, thoracic and mediastinal disorders
Dyspnoea

Gastrointestinal disorders
Diarrhoea, nausea, vomiting, flatulence
Abdominal pain, increased amylase, pancreatitis

Hepato-biliary disorders
Increased liver enzymes (ALT, AST, gamma GT), hepatitis

Skin and subcutaneous tissue disorders
Rash, pruritus

Musculoskeletal and connective tissue disorders
Myopathy, osteomalacia (both associated with proximal renal tubulopathy), rhabdomyolysis, muscular weakness

Renal and urinary disorders
Renal insufficiency, renal failure, acute renal failure, Fanconi syndrome, proximal tubulopathy, proteinuria, increased creatinine, acute tubular necrosis, nephrogenic diabetes insipidus, polyuria, intestinal nephritis (including acute cases)

General disorders and administrative site conditions
Asthenia, pyrexia

b) Paediatric population
Safety and effectiveness of VIREAD in paediatric patients younger than 12 years of age or less than 35 kg with chronic hepatitis B have not been established.

Use in adolescents
Adolescents 12 Years of Age and Older with HIV-1 infection. The safety of VIREAD in adolescent patients aged 12 to less than 18 years is supported by data from one randomized trial in which VIREAD was administered to HIV1 infected treatment-experienced subjects. In this trial, the pharmacokinetic profile of VIREAD was similar to that found to be safe and effective in adult clinical trials. In Study 321, 87 treatment-experienced subjects 12 to less than 18 years of age were treated with VIREAD (N=45) or placebo (N=42) in combination with an optimized background regimen (OBR) for 48 weeks. The mean baseline CD4 cell count was 374 cells/mm 3 and the mean baseline plasma HIV-1 RNA was 4.6 log 10 copies/ml. At baseline, 90% of subjects harboured NRTI resistance-associated substitutions in their HIV-1 isolates. Overall, the trial failed to show a difference in virologic response between the VIREAD and placebo treatment groups. Subgroup analyses suggest the lack of difference in virologic response may be attributable to imbalances between treatment arms in baseline viral susceptibility to VIREAD and OBR. Although changes in HIV-1 RNA in these highly treatment-experienced subjects were less than anticipated, the comparability of the pharmacokinetic and safety data to that observed in adults supports the use of VIREAD in adolescent 12 years of age and older who weigh greater than or equal to 35 kg and whose HIV-1 isolate is expected to be sensitive to VIREAD. (17) See sections 4.4 and 4.8. Safety and effectiveness of VIREAD in patients younger than 12 years of age with HIV-1 infection have not been established.

Adolescent Patients 12 Years of Age and Older with Chronic Hepatitis B
In Study 115, 106 HBeAg negative (9 %) and positive (91 %) subjects aged 12 to less than 18 years with chronic HBV infection were randomized to receive blinded treatment with VIREAD 300 mg (N =52) or placebo (N =54) for 72 weeks. At study entry, the mean HBV DNA was 8.1 log 10 copies/ml and mean ALT was 101 U/L. Of 52 subjects treated with VIREAD, 20 subjects were nucleoside-naive and 32 subjects were nucleoside experienced. Thirty one of the 32 nucleoside-experienced subjects had prior lamivudine experience. At Week 72, 88 % (46/52) of subjects in the VIREAD group and 0 % (0/54) of subjects in the placebo group had HBV DNA <400 copies/ml. Among subjects with abnormal ALT at baseline, 74 % (26/35) of subjects receiving VIREAD had normalized ALT at Week 72 compared to 31 % (13/42) in the placebo group. One VIREAD-treated subject experienced sustained HBsAg-loss and seroconversion to anti-HBs during the first 72 weeks of study participation. Safety and effectiveness of VIREAD in patients younger than 12 years of age or less than 35 kg with chronic hepatitis B have not been established.

Symptoms
Limited clinical experience at doses higher than the therapeutic dose of VIREAD 300 mg is available. In Study 901, 600 mg VIREAD was administered to 8 patients orally for 28 days. The effects of higher doses are not known.

Treatment
If overdosage occurs the patient must be monitored for evidence of toxicity, and standard supportive treatment applied as necessary. VIREAD is efficiently removed by haemodialysis with an extraction coefficient of approximately 54 %. Following a single 300 mg dose of VIREAD, a four-hour haemodialysis session removed approximately 10 % of the administered tenofovir dose.