Viread

/ Gilead

Adults: The recommended dose of Viread for the treatment of HIV or for the treatment of chronic hepatitis B is 245 mg (one tablet) once daily taken orally with food.
Chronic hepatitis B: The optimal duration of treatment is unknown. Treatment discontinuation may be considered as follows:
– In HBeAg positive patients without cirrhosis, treatment should be administered for at least 6-12 months after HBe seroconversion (HBeAg loss and HBV DNA loss with anti-HBe detection) is confirmed or until HBs seroconversion or there is loss of efficacy. Serum ALT and HBV DNA levels should be followed regularly after treatment discontinuation to detect any late virological relapse.
– In HBeAg negative patients without cirrhosis, treatment should be administered at least until HBs seroconversion or there is evidence of loss of efficacy. With prolonged treatment for more than 2 years, regular reassessment is recommended to confirm that continuing the selected therapy remains appropriate for the patient.
Missed dose: If a patient misses a dose of Viread within 12 hours of the time it is usually taken the patient should take Viread with food as soon as possible and resume their normal dosing schedule. If a patient misses a dose of Viread by more than 12 hours and it is almost time for their next dose, the patient should not take the missed dose and simply resume the usual dosing schedule.
If the patient vomits within 1 hour of taking Viread, another tablet should be taken. If the patient vomits more than 1 hour after taking Viread they do not need to take another dose.
Paediatric population: Viread is not recommended for use in children below the age of 12 years due to insufficient data on safety and efficacy. The recommended dose for the treatment of HIV-1 in paediatric patients (12 years of age and older with body weight ≥35 kg) is 245 mg (one tablet) once daily taken orally.
The safety of Viread in paediatric patients aged 12 to <18 years is supported by data from one randomized study in which Viread was administered to HIV-1 infected treatment-experienced subjects. In this study, the pharmacokinetic profile of Viread was similar to that found to be safe and effective in adult clinical trials. In study GS-US-104-0321, 87 treatment-experienced subjects 12 to <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/mm³, and the mean baseline plasma HIV-1 RNA was 4.6 log10 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 paediatric patients ≥12 years of age who weigh ≥35 kg and whose HIV-1 isolate is expected to be sensitive to Viread. No data are currently available in paediatric patients infected with chronic hepatitis B.
Elderly: No data are available on which to make a dose recommendation for patients over the age of 65 years.
Renal impairment: Tenofovir is eliminated by renal excretion and the exposure to tenofovir increases in patients with renal dysfunction.
Adults: There are limited data on the safety and efficacy of tenofovir disoproxil fumarate in patients with moderate and severe renal impairment (creatinine clearance < 50 ml/min) and long term safety data has not been evaluated for mild renal impairment (creatinine clearance 50-80 ml/min). Therefore, in patients with renal impairment tenofovir disoproxil fumarate should only be used if the potential benefits of treatment are considered to outweigh the potential risks. Dose interval adjustments are recommended for patients with creatinine clearance < 50 ml/min.
Mild renal impairment (creatinine clearance 50-80 ml/min): Limited data from clinical studies support once daily dosing of tenofovir disoproxil fumarate in patients with mild renal impairment.
Moderate renal impairment (creatinine clearance 30-49 ml/min): Administration of 245 mg tenofovir disoproxil (as fumarate) every 48 hours is recommended based on modelling of single-dose pharmacokinetic data in HIV negative and non-HBV infected subjects with varying degrees of renal impairment, including end-stage renal disease requiring haemodialysis, but has not been confirmed in clinical studies. Therefore, clinical response to treatment and renal function should be closely monitored in these patients.
Severe renal impairment (creatinine clearance < 30 ml/min) and haemodialysis patients: Adequate dose adjustments cannot be applied due to lack of alternative tablet strengths, therefore use in this group of patients is not recommended. If no alternative treatment is available, prolonged dose intervals may be used as follows:
Severe renal impairment: 245 mg tenofovir disoproxil (as fumarate) may be administered every 72-96 hours (dosing twice a week).
Haemodialysis patients: 245 mg tenofovir disoproxil (as fumarate) may be administered every 7 days following completion of a haemodialysis session*.
These dose interval adjustments have not been confirmed in clinical studies. Simulations suggest that the prolonged dose interval using Viread 245 mg film-coated tablets is not optimal and could result in increased toxicity and possibly inadequate response. Therefore, clinical response to treatment and renal function should be closely monitored.
* Generally, once weekly dosing assuming three haemodialysis sessions per week, each of approximately 4 hours duration or after 12 hours cumulative haemodialysis.
No dosing recommendations can be given for non-haemodialysis patients with creatinine clearance < 10 ml/min.
No data are available to make dose recommendations in paediatric patients 12 years of age and older with renal impairment.
Hepatic impairment: No dose adjustment is required in patients with hepatic impairment.
If Viread is discontinued in patients with chronic hepatitis B with or without HIV co-infection, these patients should be closely monitored for evidence of exacerbation of hepatitis.
Method of administration: Viread tablets should be taken once daily, orally with food.
Patients should be instructed not to chew or split the tablets as it may impact the absorption of Viread. If patients have difficulty swallowing they can use the tip of a spoon to crush the tablet. Then mix the powder with about 100 ml (half a glass) of water, orange juice or grape juice and drink immediately.

HIV-1 infection: In combination with other antiretroviral medicinal products for the treatment of HIV-1 infected adults and paediatric patients 12 years of age and older.
The choice of Viread to treat antiretroviral experienced patients with HIV-1 infection should be based on individual viral resistance testing and/or treatment history of patients.
Hepatitis B infection: Viread 245 mg film-coated tablets are indicated for the treatment of chronic hepatitis B in adults with:
– compensated liver disease, with evidence of active viral replication, persistently elevated serum alanine aminotransferase (ALT) levels and histological evidence of active inflammation and/or fibrosis.
– decompensated liver disease.

Hypersensitivity to the active substance or to any of the excipients.

General: HIV antibody testing should be offered to all HBV infected patients before initiating tenofovir disoproxil fumarate therapy.
Patients must be advised that tenofovir disoproxil fumarate has not been proven to prevent the risk of transmission of HIV or HBV to others through sexual contact or contamination with blood. Appropriate precautions must continue to be used.
Co-administration of other medicinal products: Viread should not be administered concomitantly with other medicinal products containing tenofovir disoproxil fumarate. – Viread should not be administered concomitantly with adefovir dipivoxil. – Co-administration of tenofovir disoproxil fumarate and didanosine is not recommended.
Triple therapy with nucleosides/nucleotides: There have been reports of a high rate of virological failure and of emergence of resistance at an early stage in HIV patients when tenofovir disoproxil fumarate was combined with lamivudine and abacavir as well as with lamivudine and didanosine as a once daily regimen.
Renal impairment: Tenofovir is principally eliminated via the kidney.Renal failure, renal impairment, elevated creatinine, hypophosphataemia and proximal tubulopathy (including Fanconi syndrome) have been reported with the use of tenofovir disoproxil fumarate in clinical practice.
Renal safety with tenofovir has only been studied to a very limited degree in patients with impaired renal function ( creatinine clearance < 80 ml/min).
It is recommended that creatinine clearance is calculated in all patients prior to initiating therapy with tenofovir disoproxil fumarate and renal function (creatinine clearance and serum phosphate) is also monitored every four weeks during the first year, and then every three months. In patients at risk for renal impairment, including patients who have previously experienced renal events while receiving adefovir dipivoxil, consideration should be given to more frequent monitoring of renal function.
Patients with creatinine clearance < 50 ml/min, including haemodialysis patients: There are limited data on the safety and efficacy of tenofovir disoproxil fumarate in patients with impaired renal function. Therefore, tenofovir disoproxil fumarate should only be used if the potential benefits of treatment are considered to outweigh the potential risks. In patients with severe renal impairment (creatinine clearance < 30 ml/min) and in patients who require haemodialysis use of tenofovir is not recommended. If no alternative treatment is available, the dosing interval must be adjusted and renal function should be closely monitored.
If serum phosphate is < 1.5 mg/dl (0.48 mmol/l) or creatinine clearance is decreased to < 50 ml/min in any patient receiving tenofovir disoproxil fumarate, renal function should be re-evaluated within one week, including measurements of blood glucose, blood potassium and urine glucose concentrations. Consideration should also be given to interrupting treatment with tenofovir disoproxil fumarate in patients with creatinine clearance decreased to < 50 ml/min or decreases in serum phosphate to < 1.0 mg/dl (0.32 mmol/l).
Use of tenofovir disoproxil fumarate should be avoided with concurrent or recent use of a nephrotoxic medicinal product (e.g. aminoglycosides, amphotericin B, foscarnet, ganciclovir, pentamidine, vancomycin, cidofovir or interleukin-2). If concomitant use of tenofovir disoproxil fumarate and nephrotoxic agents is unavoidable, renal function should be monitored weekly.
Tenofovir disoproxil fumarate has not been clinically evaluated in patients receiving medicinal products which are secreted by the same renal pathway, including the transport proteins , human organic anion transporter (hOAT) 1 and 3 or MRP 4 (e.g. cidofovir, a known nephrotoxic medicinal product). These renal transport proteins may be responsible for tubular secretion and in part, renal elimination of tenofovir and cidofovir. Consequently, the pharmacokinetics of these medicinal products which are secreted by the same renal pathway including transport proteins hOAT 1 and 3 or MRP 4 might be modified if they are co-administered. Unless clearly necessary, concomitant use of these medicinal products which are secreted by the same renal pathway is not recommended, but if such use is unavoidable, renal function should be monitored weekly.
Bone effects:

Bone abnormalities such as osteomalacia which can manifest as persistent or worsening bone pain
and, which can infrequently contribute to fractures may be associated with tenofovir disoproxilinduced proximal renal tubulopathy. Tenofovir disoproxil may also cause a reduction in bone mineral density (BMD).
In HIV infected patients, in a 144-week controlled clinical study that compared tenofovir disoproxil fumarate with stavudine in combination with lamivudine and efavirenz in antiretroviral-naïve patients, small decreases in BMD of the hip and spine were observed in both treatment groups. Decreases in BMD of spine and changes in bone biomarkers from baseline were significantly greater in the tenofovir disoproxil fumarate treatment group at 144 weeks. Decreases in BMD of hip were significantly greater in this group until 96 weeks. However, there was no increased risk of fractures or evidence for clinically relevant bone abnormalities over 144 weeks in this study.
If bone abnormalities are suspected or detected then appropriate consultation should be obtained. The bone effects of Viread have not been studied in patients with chronic HBV infection.
Paediatric population: Viread may cause a reduction in BMD. The effects of tenofovir disoproxil fumarate-associated changes in BMD on long-term bone health and future fracture risk are currently unknown.
Assessment of bone mineral density (BMD) should be considered for adults and paediatric patients 12 years of age and older who have a history of pathologic bone fracture or other risk factors for osteoporosis or bone loss. 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.
In a clinical study of HIV-1 infected paediatric subjects 12 years of age and older (study GS-US-104-0321), bone effects were similar to adult subjects. Under normal circumstances BMD increases rapidly in this age group. In this study, the mean rate of bone gain was less in the VIREADtreated group compared to the placebo group. Six VIREAD treated subjects and one placebo treated subject had significant (>4%) lumbar spine BMD loss in 48 weeks. Among 28 subjects receiving 96 weeks of VIREAD, Z-scores declined by -0.341 for lumbar spine and -0.458 for total body. Skeletal growth (height) appeared to be unaffected. Markers of bone turnover in VIREAD-treated paediatric
6/15 subjects 12 years of age and older suggest increased bone turnover, consistent with the effects observed in adults.
Excipients
This medicine contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially ‘sodium free’.
For full details see prescribing information.

Summary of the safety profile:
HIV-1 and hepatitis B: In patients receiving tenofovir disoproxil fumarate, 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 Viread.
HIV-1: Approximately one third of patients can be expected to experience adverse reactions following treatment with tenofovir disoproxil fumarate in combination with other antiretroviral agents. These reactions are usually mild to moderate gastrointestinal events. Approximately 1% of tenofovir disoproxil fumarate-treated patients discontinued treatment due to the gastrointestinal events.
Lactic acidosis, severe hepatomegaly with steatosis and lipodystrophy are associated with tenofovir disoproxil fumarate.
Co-administration of Viread and didanosine is not recommended as this may result in an increased risk of adverse reactions. Rarely, pancreatitis and lactic acidosis, sometimes fatal, have been reported.
Hepatitis B: Approximately one quarter of patients can be expected to experience adverse reactions following treatment with tenofovir disoproxil fumarate, most of which are mild. In clinical trials of HBV infected patients, the most frequently occurring adverse reaction to tenofovir disoproxil fumarate was nausea (5.4%). Acute exacerbation of hepatitis has been reported in patients on treatment as well as in patients who have discontinued hepatitis B therapy.
See prescribing information for full details.

Interaction studies have only been performed in adults.
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 medicinal products is low.
Concomitant use not recommended: Viread should not be administered concomitantly with other medicinal products containing tenofovir disoproxil fumarate.
Viread should not be administered concomitantly with adefovir dipivoxil.
Didanosine: Co-administration of tenofovir disoproxil fumarate and didanosine is not recommended.
Renally eliminated medicinal products: Since tenofovir is primarily eliminated by the kidneys, coadministration of tenofovir disoproxil fumarate with medicinal products that reduce renal function or compete for active tubular secretion via transport proteins hOAT 1, hOAT 3 or MRP 4 (e.g. cidofovir) may increase serum concentrations of tenofovir and/or the co-administered medicinal products.
Use of tenofovir disoproxil fumarate should be avoided with concurrent or recent use of a nephrotoxic medicinal product. Some examples include, but are not limited to, aminoglycosides, amphotericin B, foscarnet, ganciclovir, pentamidine, vancomycin, cidofovir or interleukin-2.
Given that tacrolimus can affect renal function, close monitoring is recommended when it is coadministered with tenofovir disoproxil fumarate.
See prescribing information for full details.

Pregnancy: A large amount of data on pregnant women (more than 1,000 pregnancy outcomes) indicate no malformations or foetal/neonatal toxicity associated with tenofovir disoproxil. Animal studies do not indicate reproductive toxicity. The use of tenofovir disoproxil may be considered during pregnancy if necessary.
Breast-feeding: Tenofovir has been shown to be excreted in human milk. There is insufficient information on the effects of tenofovir in newborns/infants. Breast-feeding should be discontinued during treatment with Viread.
As a general rule, it is recommended that HIV and HBV infected women do not breast-feed their infants in order to avoid transmission of HIV and HBV to the infant.
Fertility: There are limited clinical data with respect to the effect of tenofovir disoproxil fumarate on fertility. Animal studies do not indicate harmful effects of tenofovir disoproxil fumarate on fertility.

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