Tenofovir disoproxil

Cases of acute renal failure after initiation of high dose or multiple non-steroidal anti-inflammatory drugs (NSAIDs) have been reported in patients treated with tenofovir disoproxil and with risk factors for renal dysfunction. If tenofovir disoproxil is co-administered with an NSAID, renal function should be monitored adequately.

Tenofovir disoproxil 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 (see section 4.5).

Use of tenofovir disoproxil 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 and nephrotoxic agents is unavoidable, renal function should be monitored weekly.

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 in adult 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 adult patients with renal impairment tenofovir disoproxil should only be used if the potential benefits of treatment are considered to outweigh the potential risks. Administration of tenofovir disoproxil 33 mg/g granules to provide a reduced daily dose of tenofovir disoproxil is recommended for adult patients with creatinine clearance <50 ml/min, including haemodialysis patients.

Mild renal impairment (creatinine clearance 50-80 ml/min)

Limited data from clinical studies support once daily dosing of 245 mg tenofovir disoproxil in patients with mild renal impairment.

Moderate renal impairment (creatinine clearance 30-49 ml/min)

Administration of 132 mg tenofovir disoproxil 33 mg/g granules once daily is recommended.

For patients unable to take the granule formulation of tenofovir disoproxil, prolonged dose intervals using the 245 mg film-coated tablets may be used. Administration of 245 mg tenofovir disoproxil every 48 hours can be used 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

For patients with creatinine clearance 20-29 ml/min: Administration of 65 mg tenofovir disoproxil 33 mg/g granules once daily is recommended.

For patients with creatinine clearance 10-19 ml/min: Administration of 33 mg tenofovir disoproxil 33 mg/g granules once daily is recommended.

Haemodialysis patients: 16.5 mg tenofovir disoproxil 33 mg/g granules may be administered following completion of each 4-hour haemodialysis session.

These dose adjustments have not been confirmed in clinical studies. Therefore, clinical response to treatment and renal function should be closely monitored.

For patients unable to take the granule formulation of tenofovir disoproxil and with no alternative treatment available, prolonged dose intervals using the 245 mg film-coated tablets may be used as follows:

Severe renal impairment: 245 mg tenofovir disoproxil may be administered every 72-96 hours (dosing twice a week).

Haemodialysis patients: 245 mg tenofovir disoproxil 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 tenofovir disoproxil 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.

Paediatrics

The use of tenofovir disoproxil is not recommended in paediatric patients with renal impairment.

A higher risk of renal impairment has been reported in patients receiving tenofovir disoproxil in combination with a ritonavir or cobicistat boosted protease inhibitor. A close monitoring of renal function is required in these patients. In patients with renal risk factors, the co-administration of tenofovir disoproxil with a boosted protease inhibitor should be carefully evaluated.

Increased plasma concentrations of tenofovir resulting from co-administration of tenofovir disoproxil, ledipasvir/sofosbuvir and atazanavir/ritonavir may increase adverse reactions related to tenofovir disoproxil, including renal disorders. The safety of tenofovir disoproxil when used with ledipasvir/sofosbuvir and a pharmacokinetic enhancer (e.g. ritonavir or cobicistat) has not been established.

The combination should be used with caution with frequent renal monitoring, if other alternatives are not available.

Increased plasma concentrations of tenofovir resulting from co-administration of tenofovir disoproxil, ledipasvir/sofosbuvir and darunavir/ritonavir may increase adverse reactions related to tenofovir disoproxil, including renal disorders. The safety of tenofovir disoproxil when used with ledipasvir/sofosbuvir and a pharmacokinetic enhancer (e.g. ritonavir or cobicistat) has not been established.

The combination should be used with caution with frequent renal monitoring, if other alternatives are not available.

Co-administration of tenofovir disoproxil with ledipasvir/sofosbuvir, sofosbuvir/velpatasvir or sofosbuvir/velpatasvir/voxilaprevir has been shown to increase plasma concentrations of tenofovir, especially when used together with an HIV regimen containing tenofovir disoproxil and a pharmacokinetic enhancer (ritonavir or cobicistat). The safety of tenofovir disoproxil in the setting of ledipasvir/sofosbuvir, sofosbuvir/velpatasvir or sofosbuvir/velpatasvir/voxilaprevir and a pharmacokinetic enhancer has not been established. The potential risks and benefits associated with co-administration of ledipasvir/sofosbuvir, sofosbuvir/velpatasvir or sofosbuvir/velpatasvir/voxilaprevir with tenofovir disoproxil given in conjunction with a boosted HIV protease inhibitor (e.g. atazanavir or darunavir) should be considered, particularly in patients at increased risk of renal dysfunction. Patients receiving ledipasvir/sofosbuvir, sofosbuvir/velpatasvir or sofosbuvir/velpatasvir/voxilaprevir concomitantly with tenofovir disoproxil and a boosted HIV protease inhibitor should be monitored for adverse reactions related to tenofovir disoproxil.

Concomitant administration of sofosbuvir/velpatasvir and efavirenz is expected to decrease plasma concentrations of velpatasvir. Co-administration of sofosbuvir/velpatasvir with efavirenz-containing regimens is not recommended.

Increased plasma concentrations of tenofovir resulting from co-administration of tenofovir disoproxil, sofosbuvir/velpatasvir and lopinavir/ritonavir may increase adverse reactions related to tenofovir disoproxil, including renal disorders. The safety of tenofovir disoproxil when used with sofosbuvir/velpatasvir and a pharmacokinetic enhancer (e.g. ritonavir or cobicistat) has not been established.

The combination should be used with caution with frequent renal monitoring.

Increased plasma concentrations of tenofovir resulting from co-administration of tenofovir disoproxil, sofosbuvir/velpatasvir and atazanavir/ritonavir may increase adverse reactions related to tenofovir disoproxil, including renal disorders. The safety of tenofovir disoproxil when used with sofosbuvir/velpatasvir and a pharmacokinetic enhancer (e.g. ritonavir or cobicistat) has not been established.

The combination should be used with caution with frequent renal monitoring.

Increased plasma concentrations of tenofovir resulting from co-administration of tenofovir disoproxil, sofosbuvir/velpatasvir and darunavir/ritonavir may increase adverse reactions related to tenofovir disoproxil, including renal disorders. The safety of tenofovir disoproxil when used with sofosbuvir/velpatasvir and a pharmacokinetic enhancer (e.g. ritonavir or cobicistat) has not been established.

The combination should be used with caution with frequent renal monitoring.

Increased plasma concentrations of tenofovir resulting from coadministration of tenofovir disoproxil, sofosbuvir/velpatasvir/voxilaprevir and darunavir/ritonavir may increase adverse reactions related to tenofovir disoproxil, including renal disorders. The safety of tenofovir disoproxil when used with sofosbuvir/velpatasvir/voxilaprevir and a pharmacokinetic enhancer (e.g. ritonavir or cobicistat) has not been established.

The combination should be used with caution with frequent renal monitoring.

Tenofovir disoproxil should not be administered concomitantly with adefovir dipivoxil.

Co-administration of tenofovir disoproxil and didanosine is not recommended.

Increased systemic exposure to didanosine may increase didanosine related adverse reactions. Rarely, pancreatitis and lactic acidosis, sometimes fatal, have been reported. Co-administration of tenofovir disoproxil 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 co-administered with tenofovir disoproxil therapy has been associated with reports of high rates of virological failure within several tested combinations for the treatment of HIV-1 infection.

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 was combined with lamivudine and abacavir as well as with lamivudine and didanosine as a once-daily regimen.

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

Tenofovir disoproxil should not be administered concomitantly with other medicinal products containing tenofovir disoproxil or tenofovir alafenamide.

Overall, in view of the bone abnormalities associated with tenofovir disoproxil and the limitations of long-term data on the impact of tenofovir disoproxil on bone health and fracture risk, alternative treatment regimens should be considered for patients with osteoporosis that are at a high risk for fractures.

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 (see section 5.3). The use of tenofovir disoproxil may be considered during pregnancy, if necessary.

In the literature, exposure to tenofovir disoproxil in the third trimester of pregnancy has been shown to reduce the risk of HBV transmission from mother to infant if tenofovir disoproxil is given to mothers, in addition to hepatitis B immune globulin and hepatitis B vaccine in infants.

In three controlled clinical trials, a total of 327 pregnant women with chronic HBV infection were administered tenofovir disoproxil (245 mg) once daily from 28 to 32 weeks gestation through 1 to 2 months postpartum; women and their infants were followed for up to 12 months after delivery. No safety signal has emerged from these data.

Generally, if the newborn is adequately managed for hepatitis B prevention at birth, a mother with hepatitis B may breast-feed her infant.

Tenofovir is excreted in human milk at very low levels and exposure of infants through breast milk is considered negligible. Although long-term data is limited, no adverse reactions have been reported in breastfed infants, and HBV-infected mothers using tenofovir disoproxil may breastfeed.

In order to avoid transmission of HIV to the infant it is recommended that women living with HIV do not breast-feed their infants.

Fertility

There are limited clinical data with respect to the effect of tenofovir disoproxil on fertility. Animal studies do not indicate harmful effects of tenofovir disoproxil on fertility.

No studies on the effects on the ability to drive and use machines have been performed. However, patients should be informed that dizziness has been reported during treatment with tenofovir disoproxil.

Summary of the safety profile

HIV-1 and hepatitis B

In patients receiving tenofovir disoproxil, rare events of renal impairment, renal failure and uncommon events of 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.

HIV-1

Approximately one third of patients can be expected to experience adverse reactions following treatment with tenofovir disoproxil in combination with other antiretroviral agents. These reactions are usually mild to moderate gastrointestinal events. Approximately 1% of tenofovir disoproxil-treated adult patients discontinued treatment due to the gastrointestinal events.

Hepatitis B

Approximately one quarter of patients can be expected to experience adverse reactions following treatment with tenofovir disoproxil, most of which are mild. In clinical trials of HBV infected patients, the most frequently occurring adverse reaction to tenofovir disoproxil 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.

Tabulated summary of adverse reactions

Assessment of adverse reactions for tenofovir disoproxil is based on safety data from clinical studies and post-marketing experience. All adverse reactions are presented in the table below.

HIV-1 clinical studies

Assessment of adverse reactions from HIV-1 clinical study data is based on experience in two studies in 653 treatment-experienced patients receiving treatment with tenofovir disoproxil (n=443) or placebo (n=210) in combination with other antiretroviral medicinal products for 24 weeks and also in a double-blind comparative controlled study in which 600 treatment-naïve patients received treatment with tenofovir disoproxil 245 mg (n=299) or stavudine (n=301) in combination with lamivudine and efavirenz for 144 weeks.

Hepatitis B clinical studies

Assessment of adverse reactions from HBV clinical study data is primarily based on experience in two double-blind comparative controlled studies in which 641 adult patients with chronic hepatitis B and compensated liver disease received treatment with tenofovir disoproxil 245 mg daily (n=426) or adefovir dipivoxil 10 mg daily (n=215) for 48 weeks. The adverse reactions observed with continued treatment for 384 weeks were consistent with the safety profile of tenofovir disoproxil. After an initial decline of approximately -4.9 ml/min (using Cockcroft-Gault equation) or -3.9 ml/min/1.73 m² (using modification of diet in renal disease [MDRD] equation) after the first 4 weeks of treatment, the rate of annual decline post baseline of renal function reported in tenofovir disoproxil treated patients was -1.41 ml/min per year (using Cockcroft-Gault equation) and -0.74 ml/min/1.73 m² per year (using MDRD equation).

Patients with decompensated liver disease

The safety profile of tenofovir disoproxil in patients with decompensated liver disease was assessed in a double-blind active controlled study (GS-US-174-0108) in which adult patients received treatment with tenofovir disoproxil (n=45) or emtricitabine plus tenofovir disoproxil (n=45) or entecavir (n=22) for 48 weeks.

In the tenofovir disoproxil treatment arm, 7% of patients discontinued treatment due to an adverse event; 9% of patients experienced a confirmed increase in serum creatinine of ≥0.5 mg/dl or confirmed serum phosphate of <2 mg/dl through week 48; there were no statistically significant differences between the combined tenofovir-containing arms and the entecavir arm. After 168 weeks, 16% (7/45) of the tenofovir disoproxil group, 4% (2/45) of the emtricitabine plus tenofovir disoproxil group, and 14% (3/22) of the entecavir group experienced tolerability failure. Thirteen percent (6/45) of the tenofovir disoproxil group, 13% (6/45) of the emtricitabine plus tenofovir disoproxil group, and 9% (2/22) of the entecavir group had a confirmed increase in serum creatinine ≥0.5 mg/dl or confirmed serum phosphate of <2 mg/dl.

At week 168, in this population of patients with decompensated liver disease, the rate of death was of 13% (6/45) in the tenofovir disoproxil group, 11% (5/45) in the emtricitabine plus tenofovir disoproxil group and 14% (3/22) in the entecavir group. The rate of hepatocellular carcinoma was 18% (8/45) in the tenofovir disoproxil group, 7% (3/45) in the emtricitabine plus tenofovir disoproxil group and 9% (2/22) in the entecavir group.

Subjects with a high baseline CPT score were at higher risk of developing serious adverse events.

Patients with lamivudine-resistant chronic hepatitis B

No new adverse reactions to tenofovir disoproxil were identified from a randomised, double-blind study (GS-US-174-0121) in which 280 lamivudine-resistant patients received treatment with tenofovir disoproxil (n=141) or emtricitabine/tenofovir disoproxil (n=139) for 240 weeks.

The adverse reactions with suspected (at least possible) relationship to treatment are listed below by body system organ class and frequency. Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness. Frequencies are defined as very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100) or rare (≥1/10,000 to <1/1,000).

Table 2. Tabulated summary of adverse reactions 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 but not observed in randomised controlled clinical trials or the tenofovir disoproxil expanded access program. The frequency category was estimated from a statistical calculation based on the total number of patients exposed to tenofovir disoproxil in randomised controlled clinical trials and the expanded access program (n=7,319).

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. 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 experiencing incomplete recovery of renal function despite tenofovir disoproxil discontinuation.

Lactic acidosis

Cases of lactic acidosis have been reported with tenofovir disoproxil alone or in combination with other antiretrovirals. Patients with predisposing factors such as patients with decompensated liver disease, or patients receiving concomitant medications known to induce lactic acidosis are at increased risk of experiencing severe lactic acidosis during tenofovir disoproxil treatment, including fatal outcomes.

HIV-1

Metabolic parameters

Weight and levels of blood lipids and glucose may increase during antiretroviral therapy.

Immune reactivation syndrome

In HIV infected patients with severe immune deficiency at the time of initiation of CART, an inflammatory reaction to asymptomatic or residual opportunistic infections may arise. Autoimmune disorders (such as Graves' disease and autoimmune hepatitis) have also been reported; however, the reported time to onset is more variable and these events can occur many months after initiation of treatment.

Osteonecrosis

Cases of osteonecrosis have been reported, particularly in patients with generally acknowledged risk factors, advanced HIV disease or long-term exposure to CART. The frequency of this is unknown.

Hepatitis B

Exacerbations of hepatitis during treatment: In studies with nucleoside-naïve 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. ALT elevations had a median time to onset of 8 weeks, resolved with continued treatment, and, in a majority of cases, were associated with a ≥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.

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.

Paediatric population

HIV-1

Assessment of adverse reactions is based on two randomised trials (studies GS-US-104-0321 and GS-US-104-0352) in 184 HIV-1 infected paediatric patients (aged 2 to <18 years) who received treatment with tenofovir disoproxil (n=93) or placebo/active comparator (n=91) in combination with other antiretroviral agents for 48 weeks. The adverse reactions observed in paediatric patients who received treatment with tenofovir disoproxil were consistent with those observed in clinical studies of tenofovir disoproxil in adults.

Reductions in BMD have been reported in paediatric patients. In HIV-1 infected adolescents, the BMD Z-scores observed in subjects who received tenofovir disoproxil were lower than those observed in subjects who received placebo. In HIV-1 infected children, the BMD Z-scores observed in subjects who switched to tenofovir disoproxil were lower than those observed in subjects who remained on their stavudine- or zidovudine-containing regimen.

In study GS-US-104-0352, 8 out of 89 paediatric patients (9.0%) exposed to tenofovir disoproxil (median tenofovir disoproxil exposure 331 weeks) discontinued study drug due to renal adverse events. Five subjects (5.6%) had laboratory findings clinically consistent with proximal renal tubulopathy, 4 of whom discontinued tenofovir disoproxil therapy. Seven patients had estimated glomerular filtration rate (GFR) values between 70 and 90 mL/min/1.73 m². Among them, 3 patients experienced a clinically meaningful decline in estimated GFR which improved after discontinuation of tenofovir disoproxil.

Chronic hepatitis B

Assessment of adverse reactions is based on a randomised study (study GS-US-174-0115) in 106 adolescent patients (12 to <18 years of age) with chronic hepatitis B receiving treatment with tenofovir disoproxil 245 mg (n=52) or placebo (n=54) for 72 weeks and a randomised study (Study GS-US-174-0144) in 89 patients with chronic hepatitis B (2 to <12 years of age) receiving treatment with tenofovir disoproxil (n=60) or placebo (n=29) for 48 weeks. The adverse reactions observed in paediatric patients who received treatment with tenofovir disoproxil were consistent with those observed in clinical studies of tenofovir disoproxil in adults.

Reductions in BMD have been observed in HBV infected paediatric patients 2 to <18 years of age. The BMD Z-scores observed in subjects who received tenofovir disoproxil were lower than those observed in subjects who received placebo.

Other special population(s)

Elderly

Tenofovir disoproxil has not been studied 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.

Patients with renal impairment

Since tenofovir disoproxil can cause renal toxicity, close monitoring of renal function is recommended in adult patients with renal impairment treated with tenofovir disoproxil. The use of tenofovir disoproxil is not recommended in paediatric patients with renal impairment.