Drug Class Description

Generic Name

Drug Description

Presentation

Indications

HIV1 infection

Viread is indicated in combination with other antiretroviral medicinal products for the treatment of HIV1 infected adults over 18 years of age.

The demonstration of benefit of Viread in HIV1 infection is based on results of one study in treatmentnaïve patients, including patients with a high viral load (> 100,000 copies/ml) and studies in which Viread was added to stable background therapy (mainly tritherapy) in antiretroviral pre-treated patients experiencing early virological failure (< 10,000 copies/ml, with the majority of patients having < 5,000 copies/ml).

The choice of Viread to treat antiretroviral experienced patients with HIV1 infection should be based on individual viral resistance testing and/or treatment history of patients.

Hepatitis B infection

Viread is 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.

Adult Dosage

Therapy should be initiated by a physician experienced in the management of HIV infection and/or treatment of chronic hepatitis B.

In exceptional circumstances in patients having particular difficulty in swallowing, Viread can be administered following disintegration of the tablet in at least 100 ml of water, orange juice or grape juice.

Adults: The recommended dose 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 612 months after HBe seroconversion (HBeAg loss and HBV DNA loss with antiHBe 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.

Paediatric patients: Viread is not recommended for use in children below the age of 18 years due to insufficient data on safety and efficacy.

Renal insufficiency: Tenofovir is eliminated by renal excretion and the exposure to tenofovir increases in patients with renal dysfunction. 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 eva luated for mild renal impairment (creatinine clearance 5080 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 5080 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 3049 ml/min): Administration of 245 mg tenofovir disoproxil (as fumarate) every 48 hours is recommended based on modelling of single-dose pharmacokinetic data in nonHIV and nonHBV 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 7296 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 adjustments have not been confirmed in clinical studies. Simulations suggest that the prolonged dose interval 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 nonhaemodialysis patients with creatinine clearance < 10 ml/min.

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 coinfection, these patients should be closely monitored for evidence of exacerbation of hepatitis.

Child Dosage

The safety and efficacy of Viread in patients under the age of 18 years have not been established (See Special Precautions). Viread must not be administered to children or adolescents until further data become available describing the safety and efficacy of tenofovir disoproxil fumarate in patients under the age of 18 years.

Elderly Dosage

No data are available on which to make a dose recommendation for patients over the age of 65 years (See Special Precautions).

Contra Indications

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

Special Precautions

General: Tenofovir disoproxil fumarate has not been studied in patients under the age of 18 or in patients over the age of 65. Elderly patients are more likely to have decreased renal function, therefore caution should be exercised when treating elderly patients with tenofovir disoproxil fumarate (see below).

HIV antibody testing should be offered to all HBV infected patients before initiating tenofovir disoproxil fumarate therapy (see below Coinfection with HIV1 and hepatitis B).

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.

Viread contains lactose monohydrate. Consequently, patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency, or glucosegalactose malabsorption should not take this medicinal product.

Coadministration of other medicinal products:

- Viread should not be administered with any other medicinal products containing tenofovir disoproxil fumarate (Truvada or Atripla).

- Viread should also not be administered concurrently with adefovir dipivoxil.

- Coadministration of tenofovir disoproxil fumarate and didanosine is not recommended. Coadministration of tenofovir disoproxil fumarate and didanosine results in a 4060% increase in systemic exposure to didanosine that may increase the risk of didanosinerelated adverse events. Rare cases of pancreatitis and lactic acidosis, sometimes fatal, have been reported. Coadministration of tenofovir disoproxil fumarate and didanosine at a dose of 400 mg daily has been associated with a significant decrease in CD4 cell count, possibly due to an intracellular interaction increasing phosphorylated (i.e. active) didanosine. A decreased dosage of 250 mg didanosine coadministered with tenofovir disoproxil fumarate therapy has been associated with reports of high rates of virological failure within several tested combinations for the treatment of HIV1 infection.

Triple therapy with nucleosides/nucleotides: There have been reports of a high rate of virological failure and of emergence of resistance at 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 function: 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 (CrCl < 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) 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-eva luated within one week, including measurements of blood glucose, blood potassium and urine glucose concentrations (see section 4.8, proximal tubulopathy). 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 interleukin2). 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 eva luated 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 coadministered. 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: In HIV infected patients, in a 144week controlled clinical study that compared tenofovir disoproxil fumarate with stavudine in combination with lamivudine and efavirenz in antiretroviralnaïve patients, small decreases in bone mineral density of the hip and spine were observed in both treatment groups. Decreases in bone mineral density of spine and changes in bone biomarkers from baseline were significantly greater in the tenofovir disoproxil fumarate treatment group at 144 weeks. Decreases in bone mineral density 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.

Bone abnormalities (infrequently contributing to fractures) may be associated with proximal renal tubulopathy. If bone abnormalities are suspected then appropriate consultation should be obtained.

Liver disease: Safety and efficacy data are very limited in liver transplant patients.

There are limited data on the safety and efficacy of tenofovir disoproxil fumarate in HBV infected patients with decompensated liver disease and who have a ChildPughTurcotte (CPT) score> 9. These patients may be at higher risk of experiencing serious hepatic or renal adverse reactions. Therefore, hepatobiliary and renal parameters should be closely monitored in this patient population.

Exacerbations of hepatitis:

Flares on treatment: Spontaneous exacerbations in chronic hepatitis B are relatively common and are characterised by transient increases in serum ALT. After initiating antiviral therapy, serum ALT may increase in some patients. In patients with compensated liver disease, these increases in serum ALT are generally not accompanied by an increase in serum bilirubin concentrations or hepatic decompensation. Patients with cirrhosis may be at a higher risk for hepatic decompensation following hepatitis exacerbation, and therefore should be monitored closely during therapy.

Flares after treatment discontinuation: Acute exacerbation of hepatitis has also been reported in patients who have discontinued hepatitis B therapy. Posttreatment exacerbations are usually associated with rising HBV DNA, and the majority appears to be selflimited. However, severe exacerbations, including fatalities, have been reported. Hepatic function should be monitored at repeated intervals with both clinical and laboratory followup for at least 6 months after discontinuation of hepatitis B therapy. If appropriate, resumption of hepatitis B therapy may be warranted. In patients with advanced liver disease or cirrhosis, treatment discontinuation is not recommended since posttreatment exacerbation of hepatitis may lead to hepatic decompensation.

Liver flares are especially serious, and sometimes fatal in patients with decompensated liver disease.

Coinfection with hepatitis C or D: There are no data on the efficacy of tenofovir in patients coinfected with hepatitis C or D virus.

Coinfection with HIV1 and hepatitis B: Due to the risk of development of HIV resistance, tenofovir disoproxil fumarate should only be used as part of an appropriate antiretroviral combination regimen in HIV/HBV coinfected patients. 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 according to standard practice. If there is evidence of worsening liver disease in such patients, interruption or discontinuation of treatment must be considered. However, it should be noted that increases of ALT can be part of HBV clearance during therapy with tenofovir, see above Exacerbations of hepatitis.

Lipodystrophy (lipoatrophy/lipomatosis): In HIV infected patients, combination antiretroviral therapy has been associated with the redistribution of body fat (lipodystrophy). The long-term consequences of these events are currently unknown. Knowledge about the mechanism is incomplete. A connection between visceral lipomatosis and protease inhibitors and lipoatrophy and nucleoside reverse transcriptase inhibitors has been hypothesised. A higher risk of lipodystrophy has been associated with individual factors such as older age, and with drug related factors such as longer duration of antiretroviral treatment and associated metabolic disturbances. Clinical examination should include eva luation for physical signs of fat redistribution. Consideration should be given to the measurement of fasting serum lipids and blood glucose. Lipid disorders should be managed as clinically appropriate.

Tenofovir is structurally related to nucleoside analogues hence the risk of lipodystrophy cannot be excluded. However, 144week clinical data from antiretroviralnaïve HIV infected patients indicate that the risk of lipodystrophy was lower with tenofovir disoproxil fumarate than with stavudine when administered with lamivudine and efavirenz.

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. The main adverse events reported are haematological disorders (anaemia, neutropenia), metabolic disorders (hyperlactataemia, hyperlipasaemia). These events are often transitory. Some late-onset neurological disorders have been reported (hypertonia, convulsion, abnormal behaviour). Whether the neurological disorders are transient or permanent is currently unknown. Any child exposed in utero to nucleoside and nucleotide analogues, even HIV negative children, should have clinical and laboratory follow-up and should be fully investigated for possible mitochondrial dysfunction in case of relevant signs or symptoms. These findings do not affect current national recommendations to use antiretroviral therapy in pregnant women to prevent vertical transmission of HIV.

Immune Reactivation Syndrome: In HIV infected patients with severe immune deficiency at the time of institution of combination antiretroviral therapy (CART), an inflammatory reaction to asymptomatic or residual opportunistic pathogens may arise and cause serious clinical conditions, or aggravation of symptoms. Typically, such reactions have been observed within the first few weeks or months of initiation of CART. Relevant examples are cytomegalovirus retinitis, generalised and/or focal mycobacterium infections, and Pneumocystis jirovecii pneumonia. Any inflammatory symptoms should be eva luated and treatment instituted when necessary.

Osteonecrosis: Although the etiology 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 HIVdisease and/or longterm 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.

Interactions

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 with any other medicinal products containing tenofovir disoproxil fumarate (Truvada or Atripla).

Viread should also not be administered concurrently with adefovir dipivoxil.

Didanosine: Coadministration of tenofovir disoproxil fumarate and didanosine is not recommended (Table 1).

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 coadministered 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 interleukin2.

Given that tacrolimus can affect renal function, close monitoring is recommended when it is coadministered with tenofovir disoproxil fumarate.

Other interactions:

Interactions between tenofovir disoproxil fumarate and protease inhibitors and antiretroviral agents other than protease inhibitors are listed in Table 1 below (increase is indicated as “↑”, decrease as “”, no change as “↔”, twice daily as “b.i.d.”, and once daily as “q.d.”).

Table 1: Interactions between tenofovir disoproxil fumarate and other medicinal products