Viread

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT VIREAD® (VIREAD®)

Composition:

Active substance: tenofovir disoproxil fumarate;

One film-coated tablet contains 300 mg of tenofovir disoproxil fumarate, equivalent to 245 mg of tenofovir disoproxil;

Excipients: pregelatinized starch; sodium croscarmellose; lactose monohydrate; microcrystalline cellulose; magnesium stearate; Opadry II White 32K18425 (lactose monohydrate; hypromellose 2910; titanium dioxide (E 171); triacetin).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: film-coated tablets, white in color, almond-shaped, with imprint «GILEAD» and «4331» on one side.

Pharmacotherapeutic group.

Antiviral agents for systemic use. Nucleoside and nucleotide reverse transcriptase inhibitors.

ATC code J05A F07.

Pharmacological properties.

Pharmacodynamics.

Mechanism of action and pharmacodynamic effects

Tenofovir disoproxil fumarate is the fumarate salt of the prodrug tenofovir disoproxil. Tenofovir disoproxil is absorbed and converted into the active substance tenofovir, which is a nucleoside monophosphate (nucleotide) analogue. Tenofovir is then converted into the active metabolite tenofovir diphosphate by constitutively expressed cellular enzymes. Tenofovir diphosphate has an intracellular half-life of 10 hours in activated and 50 hours in resting peripheral blood mononuclear cells (PBMCs). Tenofovir diphosphate inhibits HIV-1 reverse transcriptase and HBV polymerase by competing with the natural deoxyribonucleotide substrate for direct binding and by chain termination after incorporation into DNA. Tenofovir diphosphate is a weak inhibitor of cellular polymerases α, β, and γ. In in vitro assays, tenofovir at concentrations up to 300 µmol/L did not affect mitochondrial DNA synthesis or lactate production.

Data regarding HIV virus.

Antiviral activity against HIV in vitro. The concentration of tenofovir required for 50% inhibition (EC50) of the laboratory wild-type HIV-1IIIB strain is 1–6 µmol/L in lymphoid cell lines and 1.1 µmol/L against primary HIV-1 subtype B isolates in PBMCs. Tenofovir is also active against HIV-1 subtypes A, C, D, E, F, G, and O, and against HIVBaL in primary monocytes/macrophages. Tenofovir exhibits in vitro activity against HIV-2 with an EC50 of 4.9 µmol/L in MT-4 cells.

Resistance. HIV-1 strains with reduced susceptibility to tenofovir and the K65R mutation in reverse transcriptase have been selected in vitro and in some patients. Tenofovir disoproxil fumarate should be avoided in patients previously treated with antiretroviral agents who have strains with the K65R mutation (see section "Special warnings and precautions for use"). Additionally, the K70E substitution in HIV-1 reverse transcriptase results in a low level of reduced sensitivity to tenofovir.

In clinical trials in treatment-experienced patients, the anti-HIV activity of tenofovir disoproxil (fumarate) at a dose of 245 mg was evaluated against HIV-1 strains resistant to nucleoside inhibitors. Results indicate that patients whose HIV had undergone 3 or more thymidine-analogue associated mutations (TAMs), including either the M41L or L210W reverse transcriptase mutation, showed a reduced response to treatment with tenofovir disoproxil (as fumarate) at a dose of 245 mg.

Data regarding hepatitis B virus (HBV).

Antiviral activity against HBV in vitro. The in vitro antiviral activity of tenofovir against HBV was evaluated in the HepG2 2.2.15 cell line. EC50 values for tenofovir ranged from 0.14 to 1.5 µmol/L, and CC50 values (50% cytotoxic concentration) were > 100 µmol/L.

Resistance. No HBV mutations associated with resistance to tenofovir disoproxil fumarate have been identified. In cell-based assays, HBV strains carrying mutations rtV173L, rtL180M, and rtM204I/V, associated with resistance to lamivudine and telbivudine, showed fold changes in sensitivity to tenofovir of 0.7–3.4 compared to wild-type virus. HBV strains carrying mutations rtL180M, rtT184G, rtS202G/I, rtM204V, and rtM250V, associated with resistance to entecavir, showed fold changes in sensitivity to tenofovir of 0.6–6.9 compared to wild-type virus. HBV strains carrying resistance-associated mutations rtA181V and rtN236T to adefovir showed fold changes in sensitivity to tenofovir of 2.9–10 compared to wild-type virus. Viruses with the rtA181T mutation remained sensitive to tenofovir, with EC50 values 1.5-fold compared to wild-type virus.

The efficacy of tenofovir disoproxil in compensated and decompensated disease has been demonstrated by virological, biochemical, and serological responses in adult patients with HBeAg-positive and HBeAg-negative chronic hepatitis B. Patients receiving tenofovir disoproxil included treatment-naïve individuals, those previously treated with lamivudine, adefovir dipivoxil, and those with baseline resistance mutations to lamivudine and/or adefovir dipivoxil. Efficacy has also been demonstrated based on histological responses in compensated patients.

In a study (GS-US-174-0144), 89 HBeAg-negative and -positive patients aged 2 to <12 years with chronic hepatitis B received 6.5 mg/kg tenofovir disoproxil, with a maximum dose of 245 mg (n = 60), or placebo (n = 29), once daily for 48 weeks. Subjects who had not previously received tenofovir disoproxil had HBV DNA > 105 copies/mL (~4.2 log10 IU/mL) and ALT > 1.5 × upper limit of normal (ULN) at screening. At week 48, 77% (46 of 60) of patients in the tenofovir disoproxil treatment group and 7% (2 of 29) in the placebo group had HBV DNA < 400 copies/mL (69 IU/mL). ALT normalization was observed in 66% (38 of 58) of patients in the tenofovir disoproxil group compared to 15% (4 of 27) in the placebo group. Twenty-five percent (14 of 56) of patients in the tenofovir disoproxil group and 24% (7 of 29) in the placebo group achieved HBeAg seroconversion by week 48.

The response to tenofovir disoproxil treatment was comparable between treatment-naïve patients and those previously treated: 76% (38/50) and 80% (8/10) of patients, respectively.

The response to tenofovir disoproxil was also similar in patients who were HBeAg-negative and those who were HBeAg-positive at baseline: 77% (43/56) of HBeAg-positive and 75.0% (3/4) of HBeAg-negative patients achieved HBV DNA < 400 copies/mL (69 IU/mL) by week 48. Overall, the response to tenofovir disoproxil treatment was similar across genotypes A, B, C, and E [75–100% of subjects achieved HBV DNA < 400 copies/mL (69 IU/mL) by week 48], with a lower response rate in individuals infected with genotype D (55%).

After at least 48 weeks of blinded randomized treatment, each subject could transition to open-label tenofovir disoproxil treatment up to week 192. After 48 weeks, virological suppression was maintained in those receiving tenofovir disoproxil during both the blinded and open-label periods (TDF-TDF group): 83.3% (50/60) of subjects in the TDF-TDF group had HBV DNA < 400 copies/mL (69 IU/mL) at week 192. Among subjects who received placebo in the first period, the proportion with HBV DNA < 400 copies/mL increased sharply after tenofovir disoproxil treatment (PLB-TDF group): 62.1% (18/29) of subjects in the PLB-TDF group had HBV DNA < 400 copies/mL at week 192. The proportion of subjects with ALT normalization at week 192 in the TDF-TDF and PLB-TDF groups was 79.3% and 59.3%, respectively. Similar proportions of subjects in the TDF-TDF and PLB-TDF groups (33.9% and 34.5%, respectively) achieved HBeAg seroconversion by week 192. No subject in either treatment group experienced HBsAg seroconversion by week 192. Treatment response rates to tenofovir disoproxil at week 192 were maintained across all genotypes A, B, and C (80–100%) in the TDF-TDF group. At week 192, a lower response rate was still observed in subjects infected with genotype D (77%), but with improvement compared to week 48 (55%).

Pharmacokinetics.

Tenofovir disoproxil fumarate is a water-soluble ester prodrug that is rapidly converted in vivo to tenofovir and formaldehyde.

Tenofovir is intracellularly converted to tenofovir monophosphate and to the active component, tenofovir diphosphate.

Absorption

After oral administration to HIV-infected patients, tenofovir disoproxil fumarate is rapidly absorbed and converted to tenofovir. Following multiple dosing of tenofovir disoproxil fumarate with food in HIV-infected patients, mean (coefficient of variation, % [CV, %]) values for Cmax, AUC0, and Cmin of tenofovir were 326 (36.6%) ng/mL, 3,324 (41.2%) ng·h/mL, and 64.4 (39.4%) ng/mL, respectively. Maximum tenofovir concentration in serum is observed within 1 hour after administration on an empty stomach and within 2 hours when taken with food. Oral bioavailability of tenofovir disoproxil fumarate administered to patients on an empty stomach is approximately 25%. Administration of tenofovir disoproxil fumarate with a high-fat meal increases oral bioavailability, increasing AUC of tenofovir by approximately 40% and Cmax by approximately 14%. After the first dose of tenofovir disoproxil fumarate taken with a high-fat meal, median Cmax in serum ranged from 213 to 375 ng/mL. However, administration of tenofovir disoproxil fumarate with a light meal had no significant effect on tenofovir pharmacokinetics.

Distribution

After intravenous administration, the steady-state volume of distribution of tenofovir is approximately 800 mL/kg. Following oral administration of tenofovir disoproxil fumarate, tenofovir distributes into many tissues, with the highest concentrations observed in the kidneys, liver, and intestinal contents (preclinical studies). In vitro binding of tenofovir to plasma or serum proteins is less than 0.7% and 7.2%, respectively, over a concentration range of 0.01 to 25 µg/mL.

Biotransformation

In vitro studies showed that neither tenofovir disoproxil fumarate nor tenofovir are substrates of CYP450 enzymes. Furthermore, at concentrations significantly higher (approximately 300-fold) than those observed in vivo, tenofovir did not inhibit in vitro metabolism mediated by any of the major human CYP450 isoenzymes involved in drug biotransformation (CYP3A4, CYP2D6, CYP2C9, CYP2E1, or CYP1A1/2). Tenofovir disoproxil fumarate at a concentration of 100 µmol/L did not affect any CYP450 isoenzymes except CYP1A1/2, where a slight (6%), but statistically significant, decrease in CYP1A1/2 substrate metabolism was observed. Based on these data, clinically significant interactions involving tenofovir disoproxil fumarate and drugs metabolized by CYP450 are unlikely.

Elimination

Tenofovir is primarily eliminated by the kidneys through both glomerular filtration and active tubular transport, with approximately 70–80% of the administered dose excreted unchanged in urine after intravenous administration. Total clearance is approximately 230 mL/h/kg (approximately 300 mL/min); renal clearance is approximately 160 mL/h/kg (about 210 mL/min), exceeding the glomerular filtration rate. This indicates that tubular secretion is an important component of tenofovir elimination. After oral administration, the terminal half-life of tenofovir is 12 to 18 hours.

Studies have shown that tenofovir enters proximal tubular cells via human organic anion transporters (hOAT) 1 and 3 and is excreted into urine via multidrug resistant protein 4 (MRP4).

Linearity/Non-linearity

Pharmacokinetic parameters of tenofovir were independent of the dose of tenofovir disoproxil fumarate in the range of 75 to 600 mg and were not affected by repeated administration at any dose level.

Age

Pharmacokinetic studies in elderly patients (over 65 years of age) have not been conducted.

Gender

Limited pharmacokinetic data in women suggest that gender does not have a significant effect.

Ethnicity

Pharmacokinetics in different ethnic groups has not been specifically studied.

Pediatric use (age 12 to < 18)

HIV-1. Steady-state pharmacokinetic parameters of tenofovir were evaluated in 8 HIV-infected patients aged 12 to <18 years with body weight ≥ 35 kg. Mean (± SD) Cmax was 0.38±0.13 µg/mL, and AUCtau was 3.39±1.22 µg·h/mL. Tenofovir exposure in patients aged 12 to <18 years receiving daily 245 mg tenofovir disoproxil (as fumarate) was similar to that in adult patients receiving daily 245 mg tenofovir disoproxil (as fumarate).

Chronic hepatitis B. The steady-state effect of tenofovir in HBV-infected patients (aged 12 to <18 years) receiving a single oral dose of tenofovir disoproxil 245 mg (as fumarate) was similar to that in adults receiving a single oral dose of tenofovir disoproxil 245 mg (as fumarate).

Pharmacological studies of tenofovir disoproxil fumarate in tablet form have not been conducted in children under 12 years of age or in children with renal impairment.

Renal impairment

Pharmacokinetic parameters of tenofovir were determined after a single 245 mg dose of tenofovir disoproxil in 40 HIV- and HBV-uninfected patients with varying degrees of renal impairment, defined according to baseline creatinine clearance (normal renal function – CrCl > 80 mL/min; mild impairment – CrCl 50–79 mL/min; moderate – CrCl 30–49 mL/min; and severe – CrCl 10–29 mL/min). Compared to patients with normal renal function (CrCl > 80 mL/min), mean exposure (% CV) of tenofovir increased from 2,185 (12%) ng·h/mL to 3,064 (30%) ng·h/mL, 6,009 (42%) ng·h/mL, and 15,985 (45%) ng·h/mL in patients with mild, moderate, and severe renal impairment, respectively. An increased dosing interval is expected to result in higher peak plasma concentrations and lower Cmin levels in patients with renal impairment compared to those with normal renal function. The clinical significance of this is unknown.

In patients with end-stage renal disease (ESRD) (CrCl < 10 mL/min) requiring hemodialysis, tenofovir concentrations significantly increased between dialysis sessions over 48 hours, reaching a mean Cmax of 1,032 ng/mL and a mean AUC0–48h of 42,857 ng·h/mL.

It is recommended that the dosing interval of tenofovir disoproxil 245 mg (as fumarate) be adjusted in adult patients with creatinine clearance < 50 mL/min and in patients with ESRD requiring dialysis (see section "Dosage and administration").

The pharmacokinetics of tenofovir in patients on hemodialysis (CrCl < 10 mL/min) and in patients with ESRD managed by peritoneal or other forms of dialysis have not been studied.

The pharmacokinetics of tenofovir in pediatric patients with renal impairment have not been studied. There are no data on dosage recommendations (see "Dosage and administration" and "Special warnings and precautions for use").

Hepatic impairment

A single 245 mg dose of tenofovir disoproxil was administered to HIV- and HBV-uninfected adult patients with varying degrees of hepatic impairment, classified according to the Child-Pugh-Turcotte classification. Pharmacokinetic parameters of tenofovir were not significantly altered in patients with hepatic impairment, indicating that dose adjustment is not required. Mean (% CV) values for Cmax and AUC0–∞ of tenofovir were 223 (34.8%) ng/mL and 2,050 (50.8%) ng·h/mL, respectively, in individuals without hepatic impairment, 289 (46.0%) ng/mL and 2,310 (43.5%) ng·h/mL in those with moderate hepatic impairment, and 305 (24.8%) ng/mL and 2,740 (44.0%) ng·h/mL in those with severe hepatic impairment.

Intracellular pharmacokinetics

In non-replicating human peripheral blood mononuclear cells, the half-life of tenofovir diphosphate is approximately 50 hours, whereas in phytohemagglutinin-stimulated PBMCs, it is approximately 10 hours.

Clinical characteristics.

Indications.

HIV-1 infection

Viread tablets are indicated for the treatment of HIV-1 infected adults in combination with other antiretroviral medicinal products.

Viread tablets are indicated for the treatment of HIV-1 infected children aged 12 to < 18 years with resistance to nucleoside reverse transcriptase inhibitors (NRTIs) or toxicity precluding the use of first-line agents.

The selection of Viread for the treatment of HIV-1 infected patients previously treated with antiretroviral agents should be based on individual data from viral resistance testing and/or patient treatment history.

Hepatitis B

Viread is indicated for the treatment of chronic hepatitis B in adults with:

• compensated liver disease, evidence of active viral replication, persistently elevated serum alanine aminotransferase (ALT) levels, and histological signs of active inflammation and/or fibrosis (see section "Pharmacodynamics");
• documented lamivudine-resistant hepatitis B (see sections "Adverse reactions" and "Pharmacodynamics");
• decompensated liver disease (see sections "Adverse reactions", "Special precautions", and "Pharmacodynamics").

Viread is indicated for the treatment of chronic hepatitis B in children aged 12 to < 18 years with:

• compensated liver disease, evidence of active immune system disease, i.e. active viral replication and persistently elevated serum alanine aminotransferase (ALT) levels or histological signs of moderate to severe active inflammation and/or fibrosis. Information regarding the decision to initiate treatment in pediatric patients is provided in sections "Dosage and administration", "Special precautions", "Adverse reactions", and "Pharmacodynamics".

Contraindications.

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

Pediatric age under 12 years.

Interaction with other medicinal products and other forms of interaction.

Interaction studies have been conducted only in adults.

Based on in vitro data and the known elimination pathway of tenofovir, the likelihood of CYP450-mediated interactions involving tenofovir and other medicinal products is low.

Not recommended for concomitant use. Viread should not be used with other medicinal products containing tenofovir disoproxil fumarate or tenofovir alafenamide.

Viread should not be used concomitantly with adefovir dipivoxil.

Didanosine. Concomitant use of tenofovir disoproxil fumarate and didanosine is not recommended (see section "Special precautions" and Table 1).

Medicinal products excreted by the kidneys. Since tenofovir is primarily eliminated by the kidneys, concomitant use of tenofovir disoproxil fumarate with medicinal products that reduce renal filtration or compete for active tubular secretion via hOAT1, hOAT3, or MRP4 transport proteins (e.g., cidofovir) may increase serum concentrations of tenofovir and/or of the co-administered medicinal products.

Concomitant or recent use of nephrotoxic medicinal products with tenofovir disoproxil fumarate should be avoided. These include, for example, aminoglycosides, amphotericin B, foscarnet, ganciclovir, pentamidine, vancomycin, cidofovir, and interleukin-2 (see section "Special precautions").

Given that tacrolimus may affect renal function, special monitoring is recommended when used concomitantly with tenofovir disoproxil fumarate.

Other interactions. Interactions between tenofovir disoproxil fumarate and other medicinal products are presented in Table 1 below (increases are indicated by "↑", decreases by "↓", no change by "↔", twice daily by "b.i.d.", and once daily by "q.d.").

Table 1

Interactions between tenofovir disoproxil fumarate and other medicinal products

1 Data obtained with concomitant use with ledipasvir/sofosbuvir. Sequential administration (12 hours apart) yielded similar results.

2 Predominant circulating metabolite of sofosbuvir.

3 The study was conducted with an additional dose of voxilaprevir 100 mg to achieve voxilaprevir exposures expected in patients infected with hepatitis C virus.

Studies conducted with other medicinal products. No clinically significant pharmacokinetic interactions were observed when tenofovir disoproxil fumarate was administered concomitantly with emtricitabine, lamivudine, indinavir, efavirenz, nelfinavir, saquinavir (ritonavir-boosted), methadone, ribavirin, rifampicin, tacrolimus, and the hormonal contraceptive norgestimate/ethinylestradiol.

Tenofovir disoproxil fumarate should be taken with food, as food increases the bioavailability of tenofovir (see section "Pharmacokinetics").

Special precautions for use.

General

Prior to initiating tenofovir disoproxil fumarate therapy, HIV antibody testing should be offered to all HBV-infected patients (see below "HIV-1 and hepatitis B co-infection").

Hepatitis B. Patients should be informed that there is no evidence that tenofovir disoproxil fumarate prevents the risk of transmission of HBV to others through sexual contact or blood exposure. Appropriate precautions should continue to be used.

Concomitant use with other medicinal products

• Viread should not be used with other medicinal products containing tenofovir disoproxil fumarate or tenofovir alafenamide.
• Viread should not be used concomitantly with adefovir dipivoxil.
• Concomitant use of tenofovir disoproxil fumarate and didanosine is not recommended (see section "Interaction with other medicinal products and other forms of interaction").

Triple nucleoside/nucleotide therapy

Reports have indicated a high rate of early virological failure and emergence of resistance in HIV patients when tenofovir disoproxil fumarate was combined with lamivudine and abacavir, as well as with lamivudine and didanosine administered once daily.

Renal and bone effects in adults

Renal effects

Tenofovir is primarily eliminated by the kidneys. Cases of renal failure, renal impairment, elevated creatinine levels, hypophosphatemia, and proximal tubulopathy (including Fanconi syndrome) have been reported with tenofovir disoproxil fumarate in clinical practice (see section "Adverse reactions").

Monitoring of renal function

Estimation of creatinine clearance should be performed in all patients prior to initiating tenofovir disoproxil fumarate therapy, and renal function (creatinine clearance and serum phosphate levels) should be monitored at 2 to 4 weeks after starting treatment, at 3 months, and then every 3–6 months in patients without risk factors for renal impairment. More frequent monitoring of renal function is required in patients at increased risk of renal dysfunction.

Treatment of renal disorders

If serum phosphate levels are < 1.5 mg/dL (0.48 mmol/L) or creatinine clearance decreases to < 50 mL/min in any adult patient receiving tenofovir disoproxil fumarate, renal function should be reassessed within 1 week, including measurement of blood glucose, blood potassium, and urine glucose (see section "Adverse reactions", proximal tubulopathy). Discontinuation of tenofovir disoproxil fumarate should also be considered in adult patients with creatinine clearance reduced to < 50 mL/min or serum phosphate levels reduced to < 1.0 mg/dL (0.32 mmol/L). Interruption of tenofovir disoproxil fumarate therapy should also be considered in cases of progressive decline in renal function if no other cause is identified.

Concomitant use and risk of renal toxicity

Concomitant use of tenofovir disoproxil fumarate with nephrotoxic medicinal products (e.g., aminoglycosides, amphotericin B, foscarnet, ganciclovir, pentamidine, vancomycin, cidofovir, and interleukin-2) should be avoided. If concomitant use of tenofovir disoproxil fumarate and nephrotoxic agents cannot be avoided, renal function should be monitored weekly.

Cases of acute renal failure after initiation of high-dose non-steroidal anti-inflammatory drugs (NSAIDs) or multiple NSAIDs have been reported in patients receiving tenofovir disoproxil fumarate, particularly in those with risk factors for renal impairment. When Viread is used concomitantly with NSAIDs, renal function should be appropriately monitored.

An increased risk of renal failure has been observed in patients receiving tenofovir disoproxil fumarate in combination with ritonavir-boosted or cobicistat-boosted protease inhibitors. Careful monitoring of renal function is required in these patients (see section "Interaction with other medicinal products and other forms of interaction"). Concomitant use of tenofovir disoproxil fumarate with boosted protease inhibitors should be carefully evaluated in patients with risk factors for renal impairment.

Clinical evaluations of tenofovir disoproxil fumarate have not been conducted in patients receiving medicinal products that are eliminated by the same renal pathway, including human organic anion transporters (hOAT) 1 and 3 or MRP 4 (e.g., cidofovir – a known nephrotoxic agent). These renal transport proteins may be involved in tubular secretion and partially in renal elimination of both tenofovir and cidofovir. Therefore, the pharmacokinetics of medicinal products eliminated by the same renal pathway, including hOAT 1 and 3 or MRP 4 transporters, may be altered with concomitant administration. Concomitant use of medicinal products eliminated by the same renal pathway is not recommended unless clearly necessary. If such concomitant use cannot be avoided, renal function should be monitored weekly (see section "Interaction with other medicinal products and other forms of interaction").

Renal impairment

The renal safety of tenofovir disoproxil fumarate has been very limitedly studied in adult patients with impaired renal function (creatinine clearance < 80 mL/min).

Adult patients with creatinine clearance < 50 mL/min, including patients on haemodialysis

There are limited data on the safety of tenofovir disoproxil fumarate in patients with renal impairment. Therefore, tenofovir disoproxil fumarate should only be prescribed when the potential benefit outweighs the potential risks. Tenofovir disoproxil fumarate is not recommended for patients with acute renal failure (creatinine clearance < 30 mL/min) or those requiring haemodialysis. If no alternative treatment is available, the dosing interval should be adjusted and renal function should be closely monitored (see sections "Posology and method of administration" and "Pharmacokinetics").

Bone effects

Bone abnormalities, such as osteomalacia, which may present as persistent or worsening bone pain and rarely may lead to fractures, may be associated with tenofovir disoproxil-induced proximal renal tubulopathy (see section "Adverse reactions").

In HIV- or hepatitis B virus-infected patients, randomized controlled trials up to 144 weeks in duration have observed a decrease in bone mineral density (BMD) during treatment with tenofovir disoproxil (see sections "Adverse reactions" and "Pharmacological properties"). BMD generally increased after discontinuation of treatment.

In other studies (prospective and crossover), the most pronounced decrease in BMD was observed in patients receiving tenofovir disoproxil fumarate as part of a regimen containing a boosted protease inhibitor.

Overall, considering bone abnormalities associated with tenofovir disoproxil and limited long-term data on the impact of tenofovir disoproxil fumarate on bone health and fracture risk, alternative treatment regimens should be considered for patients with osteoporosis or a history of bone fractures. If bone abnormalities are suspected, appropriate consultations should be obtained.

Renal and bone effects in the paediatric population

There are uncertainties regarding the long-term effects of renal and bone toxicity. In addition, reversibility of renal toxicity cannot be fully established. Therefore, a multidisciplinary approach is recommended to adequately weigh the individual benefit-risk ratio of treatment, make decisions regarding appropriate monitoring during treatment (including decisions on treatment discontinuation), and consider the need for dietary supplements.

Renal effects

During clinical trials in HIV-infected children aged 2 to < 12 years, adverse renal reactions associated with proximal renal tubulopathy were reported (see sections "Special precautions for use" and "Pharmacodynamics").

Monitoring of renal function

Renal function (serum creatinine and phosphate) should be assessed prior to initiation of treatment and monitored during treatment as in adults (see above).

Treatment of renal impairment

If serum phosphate levels are confirmed to be < 3.0 mg/dL (0.96 mmol/L) in any paediatric patient receiving tenofovir disoproxil fumarate, renal function should be evaluated within one week, including measurement of blood glucose, blood potassium, and urine glucose (see section "Adverse reactions", proximal tubulopathy). If renal abnormalities are suspected or detected, consultation with a nephrologist is required to consider the possibility of interrupting treatment with tenofovir disoproxil fumarate. Interruption of tenofovir disoproxil fumarate therapy should also be considered in cases of progressive decline in renal function if no other cause is identified.

Concomitant use and risk of renal toxicity

See above recommendations for adults.

Renal impairment

Tenofovir disoproxil fumarate is not recommended in children with renal impairment (see section "Posology and method of administration"), and therefore should not be prescribed to such paediatric patients. Treatment should be discontinued in children who develop renal impairment during therapy with tenofovir disoproxil fumarate.

Bone effects

Viread may cause a decrease in BMD. The long-term impact of BMD changes associated with tenofovir disoproxil fumarate on bone health and future fracture risk is uncertain (see section "Pharmacodynamics").

If bone abnormalities are detected or suspected in children, consultation with an endocrinologist and/or nephrologist is required.

Liver diseases

Data on safety and efficacy in patients with liver transplantation are very limited.

Safety and efficacy data for tenofovir disoproxil fumarate in patients with hepatitis B infection and decompensated liver disease with a Child-Pugh-Turcotte score > 9 are limited. These patients have a higher risk of serious hepatic and renal adverse reactions. Therefore, hepatic and renal parameters should be monitored more closely in this patient population.

Hepatitis flare

Flare during treatment. Spontaneous flares of chronic hepatitis B are relatively common and are characterized by a transient increase in serum alanine aminotransferase (ALT) levels. After initiation of antiviral therapy, serum ALT levels may increase in some patients (see section "Adverse reactions"). In patients with compensated liver disease, these ALT elevations generally do not coincide with increased serum bilirubin or hepatic decompensation. Patients with liver cirrhosis have an increased risk of hepatic decompensation following hepatitis flare and therefore require careful monitoring during treatment.

Flare after discontinuation of treatment. Acute hepatitis flares have also been reported in patients who discontinued hepatitis B treatment. Post-treatment flares are usually associated with increased HBV DNA levels, and most are self-limiting. However, severe flares, including fatal cases, have been reported. Liver function should be monitored monthly by clinical and laboratory parameters for 6 months after discontinuation of hepatitis B treatment. Reinitiation of hepatitis B treatment may be considered if necessary. Discontinuation of treatment is not recommended in patients with advanced liver disease or cirrhosis, as post-treatment hepatitis flare may lead to hepatic decompensation.

In patients with decompensated liver disease, hepatitis flares are particularly serious and sometimes fatal.

Co-infection with hepatitis C or D. Data on the efficacy of tenofovir in patients with co-infection with hepatitis C or D virus are lacking.

HIV-1 and hepatitis B co-infection. Due to the risk of HIV resistance, tenofovir disoproxil fumarate should be used in HIV/HBV co-infected patients only as part of an appropriate antiretroviral combination regimen. Patients with prior liver function abnormalities, including chronic active hepatitis, have a higher frequency of liver function disturbances during combination antiretroviral therapy (cART), and should be monitored according to standard practice. If there is evidence of worsening liver disease in these patients, interruption or discontinuation of treatment should be considered. However, it should be noted that ALT elevation may be part of viral clearance in patients with hepatitis B during tenofovir treatment (see above "Hepatitis flare").

Use with specific antiviral agents for hepatitis C

Elevated plasma concentrations of tenofovir are observed when tenofovir disoproxil fumarate is used with ledipasvir/sofosbuvir, sofosbuvir/velpatasvir, or sofosbuvir/velpatasvir/voxilaprevir, especially when used in combination with an HIV regimen containing tenofovir disoproxil fumarate and a pharmacokinetic booster (ritonavir or cobicistat). The safety of using tenofovir disoproxil fumarate with ledipasvir/sofosbuvir, sofosbuvir/velpatasvir, or sofosbuvir/velpatasvir/voxilaprevir and a pharmacokinetic booster has not been established. The potential risks and benefits of concomitant use of ledipasvir/sofosbuvir, sofosbuvir/velpatasvir, or sofosbuvir/velpatasvir/voxilaprevir with tenofovir disoproxil fumarate, prescribed in combination with a boosted HIV protease inhibitor (e.g., atazanavir or darunavir), should be carefully considered, particularly in patients at increased risk of renal impairment. Patients receiving ledipasvir/sofosbuvir, sofosbuvir/velpatasvir, or sofosbuvir/velpatasvir/voxilaprevir together with tenofovir disoproxil fumarate in combination with a boosted HIV protease inhibitor should be monitored for adverse reactions associated with tenofovir disoproxil fumarate.

Body mass and metabolism parameters

During antiretroviral therapy, increases in body weight and blood lipid and glucose levels may be observed in patients. These changes may be partly associated with therapy and partly with lifestyle. Regarding lipids, there is evidence in some cases of a treatment effect, whereas for weight gain, there is no substantial evidence linking it to any specific treatment. Monitoring of blood lipids and glucose should be performed according to established HIV treatment guidelines. Lipid disorders should be clinically managed.

Post-exposure mitochondrial dysfunctionin utero

Nucleoside and nucleotide analogues cause mitochondrial damage of varying degrees, particularly associated with stavudine, didanosine, and zidovudine. Cases of mitochondrial dysfunction have been reported in HIV-negative young children exposed to nucleoside analogues in utero and/or postnatally. This primarily concerns regimens containing zidovudine. The main adverse events reported were haematological disorders (anaemia, neutropenia) and metabolic disorders (hyperlactataemia, hyperlipasaemia). These events were often transient. Rarely, later-onset neurological disorders (hypertonia, seizures, abnormal behaviour) have been reported. It is currently unknown whether such neurological disorders are transient or permanent. These outcomes should be considered for any child exposed to nucleoside and nucleotide analogues associated with serious clinical disorders of unknown aetiology, particularly neurological disorders, in utero. These outcomes do not affect current national recommendations for the use of antiretroviral therapy in pregnant women to prevent vertical transmission of HIV.

Immune reconstitution syndrome

In HIV-infected patients with severe immune deficiency at the time of initiation of combination antiretroviral therapy (cART), an inflammatory response to asymptomatic or residual opportunistic pathogens may occur, which may result in serious clinical conditions or worsening of symptoms. Such reactions are typically observed within the first few weeks or months after initiation of cART. Typical examples include cytomegalovirus retinitis, generalized and/or focal mycobacterial infections, and Pneumocystis jirovecii pneumonia. Any inflammatory symptoms should be evaluated and, if necessary, appropriate treatment initiated.

Autoimmune disorders (such as Graves' disease or autoimmune hepatitis) have also been reported during immune reconstitution; however, the time to onset of disease varied widely, and these events may occur many months after initiation of treatment.

Osteonecrosis

Although the aetiology is considered multifactorial (including corticosteroid use, alcohol consumption, severe immunosuppression, high body mass index), cases of osteonecrosis have been observed, particularly in patients with advanced HIV disease and/or long-term exposure to cART. Patients should be advised to consult a physician if they experience joint pain, stiffness, or difficulty moving.

Elderly patients

The use of tenofovir disoproxil has not been studied in patients over 65 years of age. Elderly patients often have reduced renal function, and caution should be exercised when prescribing tenofovir disoproxil fumarate to these patients.

Excipients

Viread 300 mg film-coated tablets contain lactose monohydrate. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency, or glucose-galactose malabsorption should not take this medicinal product.

This medicinal product contains less than 1 mmol (23 mg) sodium per tablet, i.e., essentially "sodium-free".

Use during pregnancy or breastfeeding.

Pregnancy

A large amount of data from use in pregnant women (over 1,000 completed pregnancies) indicates no malformations or embryo/foetal toxicity associated with tenofovir disoproxil fumarate. Animal studies revealed no toxic effects on reproductive function. Tenofovir disoproxil fumarate may be used during pregnancy if necessary.

According to published data, exposure to tenofovir disoproxil in the third trimester of pregnancy reduces the risk of HBV transmission from mother to child when the mother receives tenofovir disoproxil in addition to hepatitis B immunoglobulin and hepatitis B vaccine administered to the infant.

In three controlled clinical trials, 327 pregnant women with chronic HBV infection received tenofovir disoproxil fumarate once daily from week 28 to 32 of gestation and for up to 1–2 months postpartum; women and their infants were followed for 12 months after delivery. No safety concerns were reported in these studies.

Breastfeeding

Generally, if a newborn receives adequate hepatitis B prophylaxis after birth, a mother with hepatitis B may breastfeed her child.

Tenofovir passes into human breast milk in very small amounts; the impact of the drug on the infant via breast milk is considered negligible. Although long-term data are limited, there are no reports of adverse events in infants breastfed by mothers; HBV-infected mothers taking tenofovir disoproxil fumarate may breastfeed their infants.

HIV-infected mothers are not recommended to breastfeed to prevent transmission of HIV to infants.

Fertility

The amount of clinical data on the effect of tenofovir disoproxil fumarate on fertility is limited. Animal studies showed no adverse effect of tenofovir disoproxil fumarate on fertility.

Ability to drive and use machines.

No studies on the effect on the ability to drive and use machines have been conducted. Patients should be informed that dizziness may occur during treatment with tenofovir disoproxil fumarate.

Method of Administration and Dosage

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

Dosage

HIV-1 and Chronic Hepatitis B

Adults and Children Aged 12 to < 18 Years with Body Weight ≥ 35 kg

The recommended dose for the treatment of HIV or chronic hepatitis B is 1 tablet once daily, taken orally with food.

Decisions regarding treatment of pediatric patients (children aged 12 to < 18 years) should be made after careful assessment of individual patient needs and current pediatric treatment guidelines, including baseline histological information. The benefits of long-term viral suppression through continuous therapy should be weighed against the risks associated with prolonged treatment, including the development of hepatitis B virus resistance and uncertainties regarding bone and renal toxicity with long-term use (see section "Special Warnings and Precautions for Use").

Serum ALT levels should be persistently elevated for at least 6 months prior to initiating treatment in pediatric patients with compensated liver disease due to HBeAg-positive chronic hepatitis B, and for at least 12 months in patients with HBeAg-negative disease.

Duration of Treatment in Adults and Children with Chronic Hepatitis B

The optimal duration of treatment is unknown. Criteria for discontinuation of treatment may include:

• Treatment of non-cirrhotic patients who are hepatitis B e antigen (HBeAg)-positive should continue for at least 12 months after confirmed HBe seroconversion (loss of hepatitis B e antigen and hepatitis B virus DNA, with detection of anti-HBe in two consecutive serum samples collected 3–6 months apart) or until HBs seroconversion or loss of response occurs (see section "Special Warnings and Precautions for Use"). After stopping treatment, serum ALT and hepatitis B virus DNA levels should be monitored regularly to detect any late virological relapses.
• Treatment of non-cirrhotic patients who are HBeAg-negative should continue until HBs seroconversion or loss of response occurs. Discontinuation of treatment may also be considered after achieving stable viral suppression (i.e., for at least 3 years), provided that regular monitoring of serum ALT and HBV DNA levels is performed after stopping treatment to detect possible late relapse. For prolonged treatment lasting more than 2 years, periodic re-evaluation of therapy is recommended to confirm that the chosen treatment remains appropriate for the patient.

Discontinuation of treatment is not recommended in adult patients with decompensated liver disease or cirrhosis.

Missed Dose

If a patient misses a dose of Viread and less than 12 hours have passed since the scheduled dose, the patient should take the missed dose as soon as possible with food, then resume the normal dosing schedule. If a patient misses a dose of Viread and more than 12 hours have passed since the scheduled dose (i.e., the next dose is almost due), the patient should not take the missed dose and should continue with the next scheduled dose.

If vomiting occurs within 1 hour after taking Viread, the patient should take another tablet. If vomiting occurs more than 1 hour after taking Viread, there is no need to take another tablet.

Special Patient Groups

Elderly Patients. Currently, there are no data upon which to base dosage recommendations for patients aged 65 years and older (see section "Special Warnings and Precautions for Use").

Renal Impairment. Tenofovir is eliminated via the kidneys; therefore, patients with renal dysfunction are exposed to higher tenofovir concentrations.

Adults. Data on the safety and efficacy of tenofovir disoproxil fumarate in adult patients with moderate to severe renal impairment (creatinine clearance < 50 mL/min) are limited, and long-term safety in patients with mild renal impairment (creatinine clearance 50–80 mL/min) has not been evaluated. Therefore, tenofovir disoproxil fumarate should be used in patients with renal impairment only if the potential benefit outweighs the risk. Dosing interval adjustment is recommended for adult patients with creatinine clearance < 50 mL/min, including those undergoing hemodialysis.

Mild renal impairment (creatinine clearance 50–80 mL/min). Limited clinical trial data in patients with mild renal impairment support once-daily dosing of tenofovir disoproxil fumarate.

Moderate renal impairment (creatinine clearance 30–49 mL/min). Dosing every 48 hours with 1 Viread tablet may be considered based on pharmacokinetic modeling of single-dose data in HIV-negative and hepatitis B virus-uninfected subjects with varying degrees of renal impairment, including end-stage renal disease requiring hemodialysis. However, this dosing regimen has not been clinically validated. Therefore, clinical response to treatment and renal function should be closely monitored in these patients (see sections "Special Warnings and Precautions for Use" and "Pharmacokinetics").

Patients with severe renal impairment (creatinine clearance < 30 mL/min) and patients on hemodialysis. Appropriate dose adjustment cannot be applied due to the lack of tablets with alternative active ingredient strengths; therefore, use of the drug is not recommended in these patient groups. If no alternative therapy is available, extended dosing intervals may be considered as follows:

• in patients with severe renal impairment: 1 Viread tablet every 72–96 hours (twice weekly);
• in patients on hemodialysis: 1 Viread tablet every 7 days after completion of a hemodialysis session*.

* Generally, once weekly, assuming 3 hemodialysis sessions per week, each lasting approximately 4 hours, or after 12 hours of cumulative hemodialysis.

These adjusted dosing intervals have not been clinically validated. Modeling suggests that prolonged dosing intervals of Viread tablets coated with a film coating may not be optimal and could lead to increased toxicity and possibly suboptimal response. Therefore, clinical response to treatment and renal function should be monitored (see sections "Special Warnings and Precautions for Use" and "Pharmacokinetics").

No dosage recommendations can be given for patients not on hemodialysis with creatinine clearance < 10 mL/min.

Children. The use of tenofovir disoproxil fumarate is not recommended in children with renal impairment (see section "Special Warnings and Precautions for Use").

Hepatic Impairment. No dose adjustment is required for patients with hepatic impairment (see sections "Special Warnings and Precautions for Use" and "Pharmacokinetics").

Patients with chronic hepatitis B, with or without concomitant HIV infection, should be closely monitored after discontinuation of Viread for signs of hepatitis flare (see section "Special Warnings and Precautions for Use").

Method of Administration

Viread tablets should be taken once daily orally with food.

If patients have difficulty swallowing, Viread tablets can be crushed and mixed with approximately 100 mL of water, orange juice, or grape juice and consumed immediately.

Children.

The safety and efficacy of tenofovir disoproxil fumarate in children under 12 years of age or with body weight < 35 kg have not been established. Data are lacking.

Overdose.

Symptoms

In the event of overdose, patients should be monitored for signs of toxicity (see section "Adverse Reactions"), and standard supportive treatment should be administered if necessary.

Treatment

Tenofovir can be removed by hemodialysis, with a median clearance rate of 134 mL/min. Elimination of tenofovir by peritoneal dialysis has not been studied.

Adverse Reactions

Summary of Safety Profile

HIV-1 and Hepatitis B. Rare cases of renal impairment, renal failure, and infrequent cases of proximal renal tubulopathy (including Fanconi syndrome), sometimes leading to bone abnormalities (rarely fractures), have been reported in patients receiving tenofovir disoproxil fumarate. Monitoring of renal function is recommended for patients taking Viread (see section "Special Warnings and Precautions for Use").

HIV-1. Adverse reactions during treatment with tenofovir disoproxil fumarate in combination with other antiretroviral agents may be expected in approximately one-third of patients. These are usually mild to moderate gastrointestinal events. Approximately 1% of adult patients receiving tenofovir disoproxil fumarate discontinued treatment due to gastrointestinal adverse reactions.

Hepatitis B. Adverse reactions during treatment with tenofovir disoproxil fumarate (mostly mild) may be expected in approximately 25% of patients. In clinical trials involving patients infected with hepatitis B virus, the most common adverse reaction associated with tenofovir disoproxil fumarate was nausea (5.4%).

Severe exacerbations of hepatitis have been reported in patients receiving therapy, as well as in patients who discontinued treatment for hepatitis B (see section "Special Warnings and Precautions for Use").

Summary Table of Adverse Reactions

The assessment of adverse reactions to tenofovir disoproxil fumarate is based on safety data obtained from clinical trials and post-marketing experience. All adverse reactions are listed in Table 2.

Clinical Trials in HIV-1. Assessment of adverse reactions in HIV-1 clinical trials is based on results from two studies in which 653 treatment-experienced patients received tenofovir disoproxil fumarate (n = 443) or placebo (n = 210) in combination with other antiretroviral agents for 24 weeks, and on data from a double-blind, controlled comparative trial in which 600 treatment-naive patients received 245 mg tenofovir disoproxil (as fumarate) (n = 299) or stavudine (n = 301) in combination with lamivudine and efavirenz for 144 weeks.

Clinical Trials in Hepatitis B. Assessment of adverse reactions in hepatitis B clinical trials is primarily based on results from two double-blind, controlled comparative studies in which 641 adult patients with chronic hepatitis B and compensated liver disease received 245 mg tenofovir disoproxil (as fumarate) once daily (n = 426) or adefovir dipivoxil 10 mg once daily (n = 215) for 48 weeks. Adverse reactions observed during 384 weeks of continuous treatment were consistent with the safety profile of tenofovir disoproxil fumarate. Following an initial decline of approximately 4.9 mL/min (by Cockcroft-Gault equation) or 3.9 mL/min/1.73 m² (by Modification of Diet in Renal Disease [MDRD] equation) after the first 4 weeks of treatment, the annual rate of decline in renal function from baseline reported in patients treated with tenofovir disoproxil fumarate was 1.41 mL/min/year (Cockcroft-Gault) and 0.74 mL/min/1.73 m²/year (MDRD).

Patients with Decompensated Liver Disease. The safety profile of tenofovir disoproxil fumarate in patients with decompensated liver disease was evaluated in a double-blind, active-controlled trial (GS-US-174-0108), in which adult patients received tenofovir disoproxil fumarate (n = 45), emtricitabine and tenofovir disoproxil fumarate (n = 45), or entecavir (n = 22) for 48 weeks.

In the tenofovir disoproxil fumarate group, 7% of patients discontinued treatment due to adverse reactions, and 9% of patients had confirmed increases in serum creatinine ≥ 0.5 mg/dL or confirmed serum phosphate levels < 2 mg/dL by week 48. There was no statistically significant difference between the tenofovir combination group and the entecavir group. At week 168, intolerance was observed in 16% (7 out of 45) of patients in the tenofovir disoproxil fumarate group, 4% (2 out of 45) in the emtricitabine and tenofovir disoproxil fumarate group, and 14% (3 out of 22) in the entecavir group. Confirmed increases in serum creatinine ≥ 0.5 mg/dL or confirmed serum phosphate < 2 mg/dL occurred in 13% (6 out of 45) of patients in the tenofovir disoproxil fumarate group, 13% (6 out of 45) in the emtricitabine and tenofovir disoproxil fumarate group, and 9% (2 out of 22) in the entecavir group.

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

Subjects with a high baseline score according to the Child-Pugh-Turcotte classification were reported to have a higher risk of developing serious adverse reactions (see section "Special Warnings and Precautions for Use").

Patients with Chronic Hepatitis B Resistant to Lamivudine. No new adverse reactions to tenofovir disoproxil fumarate were identified in a randomized, double-blind trial (GS-US-174-0121), in which 280 lamivudine-resistant patients received tenofovir disoproxil fumarate (n = 141) or emtricitabine/tenofovir disoproxil fumarate (n = 139) for 240 weeks.

Adverse reactions with a potential (at least possible) relationship to treatment are listed below by system organ class and frequency. Within each frequency group, adverse events are listed in order of decreasing severity. Adverse reactions by frequency are defined as: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), and rare (≥ 1/10,000 to < 1/1,000).

Table 2:
Summary table of adverse reactions associated with tenofovir disoproxil fumarate based on clinical trial and post-marketing data

1 The adverse reaction may occur as a result of proximal renal tubulopathy. It is not considered to be causally related to tenofovir disoproxil fumarate in the absence of this disorder.

2 The adverse reaction was identified during post-marketing surveillance, but was not observed during randomized controlled trials or the expanded access program with tenofovir disoproxil fumarate. The frequency category was established based on statistical calculations using the total number of patients who received tenofovir disoproxil fumarate in randomized controlled trials and the expanded access program (n = 7319).

3 The frequency of this adverse reaction was estimated based on safety data obtained from various clinical trials of tenofovir disoproxil fumarate in patients infected with hepatitis B virus. See also sections “Special warnings and precautions for use” and “Pharmacological properties”.

Description of selected adverse reactions

HIV-1 and hepatitis B.

Renal failure. Since Viread may cause renal impairment, monitoring of renal function is recommended (see sections “Special warnings and precautions for use” and “Summary of safety profile”). Proximal renal tubulopathy generally resolved or improved after discontinuation of tenofovir disoproxil fumarate. However, in some patients, the decline in creatinine clearance did not completely cease despite discontinuation of tenofovir disoproxil fumarate. Patients at risk of renal dysfunction (e.g., patients with baseline risk factors for renal impairment, patients with advanced HIV disease, or patients receiving concomitant nephrotoxic medications) have an increased risk of incomplete recovery of renal function despite discontinuation of tenofovir disoproxil fumarate (see section “Special warnings and precautions for use”).

Lactic acidosis

Cases of lactic acidosis have been reported with the use of tenofovir disoproxil as monotherapy or in combination with other antiretroviral agents. Patients with predisposing factors, such as those with decompensated liver disease or those concurrently taking other medications that can cause lactic acidosis, have an increased risk of developing severe lactic acidosis during treatment with tenofovir disoproxil, sometimes fatal.

HIV-1.

Metabolic disturbances. Body weight and levels of lipids and blood glucose may increase with antiretroviral therapy (see section “Special warnings and precautions for use”).

Immune reconstitution syndrome. In HIV-infected patients with severe immune deficiency at the time of initiation of combination antiretroviral therapy (cART), an inflammatory response to asymptomatic or residual opportunistic pathogens may occur. Autoimmune disorders (such as Graves’ disease or autoimmune hepatitis) have also been reported; however, the reported time to onset of disease has been highly variable, and these events may occur many months after initiation of treatment (see section “Special warnings and precautions for use”).

Osteonecrosis. Cases of osteonecrosis have been observed in patients with generally recognized risk factors, advanced HIV disease, or long-term exposure to cART. The frequency of occurrence of this phenomenon is unknown (see section “Special warnings and precautions for use”).

Hepatitis B.

Hepatitis flare during treatment. In studies involving nucleoside-naïve patients, ALT elevations during treatment to 10 times or more above the upper limit of normal (ULN) and to 2 times or more above baseline were observed in 2.6% of patients receiving tenofovir disoproxil fumarate. ALT elevations had a median time to onset of 8 weeks and were managed with continued treatment. In most cases, such ALT elevations were associated with a ≥ 2 log10 copies/mL decrease in viral load that preceded or coincided with the ALT elevation. Monitoring of liver function is recommended during treatment (see section “Special warnings and precautions for use”).

Hepatitis flare after discontinuation of treatment. After discontinuation of hepatitis B therapy in patients infected with hepatitis B virus, clinical and laboratory signs of hepatitis flare have occurred (see section “Special warnings and precautions for use”).

Use in children

HIV-1.

Adverse reactions were evaluated in one randomized trial (Study GS-US-104-0321) involving 87 HIV-1-infected pediatric patients (aged 12 to < 18 years) who received tenofovir disoproxil fumarate (n = 45) or placebo (n = 42) in combination with other antiretroviral agents for 48 weeks (see section “Pharmacodynamics”). Adverse reactions observed in patients aged 12 to < 18 years receiving tenofovir disoproxil fumarate were consistent with those observed in adults during clinical trials of tenofovir disoproxil fumarate (see section “Summary table of adverse reactions” and “Pharmacodynamics”).

In HIV-1-infected children, Z-scores for bone mineral density (BMD) observed during tenofovir disoproxil fumarate treatment were lower than with placebo.

In Study GS-US-104-0352, 8 of 89 pediatric patients (9.0%) receiving tenofovir disoproxil fumarate (mean duration of 331 weeks) discontinued the study drug due to renal adverse effects. Five patients (5.6%) had laboratory findings clinically consistent with proximal renal tubulopathy, four of whom discontinued tenofovir disoproxil fumarate therapy. Estimated glomerular filtration rate (eGFR) values in seven patients ranged from 70 to 90 mL/min/1.73 m². Of these, three patients experienced clinically significant decreases in eGFR, which improved after discontinuation of the drug.

Chronic hepatitis B.

Adverse reactions were evaluated in one randomized trial (Study GS-US-174-0115) involving 106 pediatric patients aged 12 to < 18 years with chronic hepatitis B who received tenofovir disoproxil 245 mg (as fumarate) (n = 52) or placebo (n = 54) for 72 weeks, and in a randomized trial (Study GS-US-174-0144) involving 89 patients aged 2 to < 12 years with chronic hepatitis B who received tenofovir disoproxil (n = 60) or placebo (n = 29) for 48 weeks. Adverse reactions observed in pediatric patients receiving tenofovir disoproxil fumarate were consistent with those observed in adults during clinical trials of tenofovir disoproxil fumarate (see section “Summary table of adverse reactions” and “Pharmacodynamics”).

Decreased BMD was observed in HBV-infected children aged 12 to < 18 years. The Z-score for BMD observed in patients receiving tenofovir disoproxil fumarate was comparable to that in patients receiving placebo (see sections “Special warnings and precautions for use” and “Pharmacodynamics”).

Other special patient groups

Elderly patients. Studies on the effect of tenofovir disoproxil fumarate in patients over 65 years of age have not been conducted. Elderly patients are more likely to have decreased renal function; therefore, caution should be exercised when administering tenofovir disoproxil fumarate to this population (see section “Special warnings and precautions for use”).

Patients with renal impairment. Since tenofovir disoproxil fumarate may lead to nephrotoxicity, renal function should be monitored in all adult patients with renal impairment who are taking Viread (see sections “Dosage and administration”, “Special warnings and precautions for use”, and “Pharmacokinetics”). The use of tenofovir disoproxil fumarate is not recommended in children with impaired renal function (see sections “Dosage and administration” and “Special warnings and precautions for use”).

If adverse reactions occur, consult your doctor.

Reporting suspected adverse reactions

Reporting suspected adverse reactions after medicine authorization is important. It allows continued monitoring of the benefit-risk balance of the medicine. Healthcare professionals, as well as patients or their legal representatives, should report suspected adverse reactions and lack of efficacy to the State Expert Centre of the Ministry of Health of Ukraine via the following link: https://aisf.dec.gov.ua.

If you have questions regarding the safety of the medicine, contact the applicant’s representative:

Representative of Delta Medical Promotions AG

43 Chornovola Street, Vyshneve, Kyiv-Sviatoshyn District, Kyiv Oblast, 08132, Ukraine.

Phone: 044 593 33 55

Fax: 044 593 33 54

Email address: [email protected]

Shelf life. 5 years.

Storage conditions. Store below 30 °C. Keep out of the reach of children.

Packaging. 30 tablets in polyethylene bottles with child-resistant closure. One bottle in a cardboard box.

Prescription status. Prescription only.

Manufacturer.

Gilead Sciences Ireland UC.

Manufacturer’s address and place of business.

IDA Business and Technology Park, Carrigtohill, Co. Cork, Ireland.