Tenofovir disoproxil fumarate
Ukraine
Table of Contents
INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT TENOFOVIR DISOPROXIL FUMARATE
Composition:
Active substance: tenofovir disoproxil fumarate;
One tablet contains 300 mg of tenofovir disoproxil fumarate, equivalent to 245 mg of tenofovir disoproxil;
Excipients: lactose monohydrate; microcrystalline cellulose; sodium croscarmellose; pregelatinized starch; magnesium stearate; coloring agent Opadry II Light Blue (Y-30-10671-A) (composition: hypromellose; indigo carmine (E 132); lactose monohydrate; titanium dioxide (E 171); triacetin).
Pharmaceutical form. Film-coated tablets.
Main physicochemical properties: film-coated tablets, light blue in color, almond-shaped, with "N" engraved on one side and "123" on the other.
Pharmacotherapeutic group. Antiviral agents for systemic use. Nucleoside and nucleotide reverse transcriptase inhibitors.
ATC code J05AF07.
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 compound, tenofovir, a nucleotide analogue monophosphate. Tenofovir is subsequently 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 state in peripheral blood mononuclear cells (PBMCs). Tenofovir diphosphate inhibits HIV-1 reverse transcriptase and HBV polymerase by competing with the natural substrate deoxyribonucleotide for direct binding and by chain termination after incorporation into DNA. Tenofovir diphosphate is a weak inhibitor of cellular DNA polymerases α, β, and γ. In in vitro assays, tenofovir at concentrations up to 300 μmol/L did not show effects on mitochondrial DNA synthesis or lactate production.
Data related to HIV virus
HIV antiviral activity 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, as well as against HIVBaL in primary monocyte/macrophage cells. Tenofovir demonstrates 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 (see "Clinical trial results"). Tenofovir disoproxil fumarate should be avoided in patients previously treated with antiretroviral agents harboring the K65R mutation (see section "Special precautions"). Additionally, the K70E substitution in HIV-1 reverse transcriptase results in a low level of reduced susceptibility 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 nucleoside inhibitor-resistant HIV-1 strains. Results indicated that patients whose HIV had accumulated 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 245 mg.
Data related to 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, with CC50 values (50% cytotoxic concentration) > 100 μmol/L.
Resistance. No HBV mutations associated with resistance to tenofovir disoproxil fumarate have been identified. In cellular assays, HBV strains carrying mutations rtV173L, rtL180M, and rtM204I/V, associated with resistance to lamivudine and telbivudine, showed tenofovir susceptibility varying from 0.7- to 3.4-fold compared to wild-type virus. HBV strains carrying mutations rtL180M, rtT184G, rtS202G/I, rtM204V, and rtM250V, associated with resistance to entecavir, showed tenofovir susceptibility varying from 0.6- to 6.9-fold compared to wild-type virus. HBV strains carrying mutations rtA181V and rtN236T, associated with resistance to adefovir, showed tenofovir susceptibility varying from 2.9- to 10-fold compared to wild-type virus. Viruses carrying 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. The patient population included treatment-naïve patients, those previously treated with lamivudine, adefovir, or dipivoxil, and patients with baseline resistance mutations to lamivudine and/or adefovir dipivoxil. Efficacy was also demonstrated based on histological responses in compensated patients.
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 then to the active component, tenofovir diphosphate.
Absorption. After oral administration to HIV-infected patients, tenofovir disoproxil fumarate is rapidly absorbed and converted to tenofovir. Administration of multiple doses of tenofovir disoproxil fumarate with food to HIV-infected patients resulted in mean (coefficient of variation, % [CV, %]) values for tenofovir Cmax, AUC0, and Cmin of 326 (36.6%) ng/mL, 3,324 (41.2%) ng·h/mL, and 64.4 (39.4%) ng/mL, respectively. Maximum tenofovir concentrations in plasma are observed within 1 hour after administration on an empty stomach and within 2 hours when administered with food. Following oral administration of tenofovir disoproxil fumarate to fasting patients, the oral bioavailability was approximately 25%. Administration of tenofovir disoproxil fumarate with a high-fat meal increased oral bioavailability, increasing tenofovir AUC by approximately 40% and Cmax by approximately 14%. After the first dose of tenofovir disoproxil fumarate administered with a high-fat meal, the median Cmax in plasma ranged from 213 to 375 ng/mL. However, administration with a light meal had no significant effect on the pharmacokinetics of tenofovir.
Distribution. Following intravenous administration, the steady-state volume of distribution of tenofovir was approximately 800 mL/kg. After 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 was less than 0.7% and 7.2%, respectively, over a concentration range of 0.01 to 25 μg/mL.
Biological transformation. 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 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 had no effect on any CYP450 isoenzymes except CYP1A1/2, where a slight (6%) but statistically significant reduction 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 via both glomerular filtration and active tubular transport, with approximately 70–80% of the dose excreted unchanged in urine after intravenous administration. Total clearance was estimated at approximately 230 mL/h/kg (approximately 300 mL/min). Renal clearance was estimated at 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 ranges from 12 to 18 hours.
Studies have shown that tenofovir is transported into the proximal tubular cell via human organic anion transporters (hOAT) 1 and 3 and excreted into urine via multidrug resistance protein 4 (MRP4).
Linearity-nonlinearity. 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) have not been conducted.
Gender. Limited pharmacokinetic data in women suggest that gender has no significant effect.
Ethnicity. Pharmacokinetics in different ethnic groups have not been specifically studied.
Use in children and adolescents
HIV-1. Steady-state pharmacokinetic parameters of tenofovir were evaluated in 8 HIV-infected adolescent patients aged 12 to 18 years with body weight ≥ 35 kg. The mean (± SD) Cmax was 0.38 ± 0.13 μg/mL, and AUCtau was 3.39 ± 1.22 μg·h/mL. Tenofovir exposure achieved in adolescent patients receiving 245 mg of tenofovir disoproxil (as fumarate) daily was similar to that achieved in adult patients receiving 245 mg of tenofovir disoproxil (as fumarate) daily.
Chronic hepatitis B. The steady-state effect of tenofovir in HBV-infected patients (aged 12 to < 18 years) who received a single oral dose of tenofovir disoproxil 245 mg (as fumarate) was similar to that achieved in adults receiving a single oral dose of tenofovir disoproxil 245 mg (as fumarate).
Pharmacological studies 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, classified according to baseline creatinine clearance (normal renal function if CrCl > 80 mL/min; mild impairment if CrCl 50–79 mL/min; moderate impairment if CrCl 30–49 mL/min; and severe impairment if CrCl 10–29 mL/min). Compared to patients with normal renal function, mean exposure (% CV) to tenofovir increased from 2,185 (12%) ng·h/mL in individuals with CrCl > 80 mL/min 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. It is expected that extending the dosing interval will 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 increased significantly 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 fumarate 245 mg be adjusted in 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 with creatinine clearance < 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 available regarding dosage recommendations (see "Dosage and administration" and "Special precautions").
Hepatic impairment. A single 245 mg dose of tenofovir disoproxil was administered to HIV- and HBV-uninfected patients with varying degrees of hepatic impairment classified according to the Child–Pugh–Turcotte (CPT) classification. Pharmacokinetic parameters of tenofovir were not significantly altered in patients with hepatic impairment, indicating no need for dose adjustment. Mean (% CV) values of Cmax and AUC0–∞ for 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
Tenofovir disoproxil fumarate tablets are indicated for the treatment of HIV-1 infected patients in combination with other antiretroviral medicinal products.
Tenofovir disoproxil fumarate tablets are indicated for the treatment of HIV-1 infected adolescents with resistance to nucleoside reverse transcriptase inhibitors (NRTIs) or toxicity precluding the use of first-line agents in patients aged 12 to < 18 years.
The choice of tenofovir disoproxil fumarate for the treatment of HIV-1 infected patients previously treated with antiretroviral agents should be based on individual resistance testing history or patient treatment history.
Hepatitis B
Tenofovir disoproxil fumarate is indicated for the treatment of chronic hepatitis B in adults with:
- compensated liver disease, with evidence of active viral replication, persistent elevation of serum alanine aminotransferase (ALT) levels, and histological evidence 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").
Tenofovir disoproxil fumarate is indicated for the treatment of chronic hepatitis B in adolescents aged 12 to < 18 years with:
- compensated liver disease, evidence of active immune system disease, i.e. active viral replication, persistent elevation of serum alanine aminotransferase (ALT) levels, and histological evidence of active inflammation and/or fibrosis (see sections "Special precautions", "Adverse reactions", and "Pharmacodynamics").
Contraindications.
Hypersensitivity to the active substance or to any of the excipients.
Children under 12 years of age.
Interaction with other medicinal products and other forms of interaction.
Interaction studies have been conducted only in adults.
Based on in vitro experimental results and the known elimination pathway of tenofovir, the likelihood of CYP450-mediated interactions between tenofovir and other medicinal products is low.
Not recommended for concomitant use. Tenofovir disoproxil fumarate should not be used with other medicinal products containing tenofovir disoproxil fumarate or tenofovir alafenamide.
Tenofovir disoproxil fumarate 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 ELIMINATED 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 concomitantly 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").
Because tacrolimus may affect renal function, special monitoring is recommended when it is used with tenofovir disoproxil fumarate.
Other interactions. Interactions between tenofovir disoproxil fumarate and other medicinal products, protease inhibitors, and non-protease inhibitor antiretrovirals are presented below in Table 1 (increases are indicated by "↑", decreases by "↓", no change by "↔", twice daily by "b.i.d.", and once daily by "q.d.").
Interactions between tenofovir disoproxil fumarate and other medicinal products
Table 1
| Medicinal product by treatment indication (dose in milligrams) |
Effect on drug levels, mean percentage change AUC, Cmax, Cmin |
Recommendation for co-administration with tenofovir disoproxil fumarate, 300 mg |
| ANTI-INFECTIVES |
||
| Antiretrovirals |
||
| Protease inhibitors |
||
| Atazanavir/ritonavir (300 q.d./100 q.d./300 q.d.) |
Atazanavir: AUC: ↓ 25 % Cmax: ↓ 28 % Cmin: ↓ 26 % Tenofovir: AUC: ↑ 37 % Cmax: ↑ 34 % Cmin: ↑ 29 % |
Dose adjustment is not recommended. Increased tenofovir exposure may enhance tenofovir-related adverse events, including renal impairment. Renal function should be closely monitored (see section "Special warnings and precautions for use"). |
| Lopinavir/ritonavir (400 b.i.d./100 b.i.d./300 q.d.) |
Lopinavir/ritonavir. No significant effect on pharmacokinetic parameters of lopinavir/ritonavir. Tenofovir: AUC: ↑ 32 % Cmax: ↔ Cmin: ↑ 51 % |
Dose adjustment is not recommended. Increased tenofovir exposure may enhance tenofovir-related adverse events, including renal impairment. Renal function should be closely monitored (see section "Special warnings and precautions for use"). |
| Darunavir/ritonavir (300/100 b.i.d./300 q.d.) |
Darunavir. No significant effect on pharmacokinetic parameters of darunavir/ritonavir. Tenofovir: AUC: ↑ 22 % Cmin: ↑ 37 % |
Dose adjustment is not recommended. Increased tenofovir exposure may enhance tenofovir-related adverse events, including renal impairment. Renal function should be closely monitored (see section "Special warnings and precautions for use"). |
| Nucleoside reverse transcriptase inhibitors (NRTIs) |
||
| Didanosine |
Co-administration of tenofovir disoproxil fumarate with didanosine results in a 40–60 % increase in systemic exposure to didanosine, which may increase the risk of didanosine-related adverse events. Rare, sometimes fatal, cases of pancreatitis and lactic acidosis have been reported. Co-administration of tenofovir disoproxil fumarate with didanosine at a dose of 400 mg daily has been associated with a significant decrease in CD4 cell count, possibly due to intracellular interaction increasing phosphorylated (i.e., active) didanosine. Reduced dosing (250 mg) of didanosine administered with tenofovir disoproxil fumarate has been associated with reports of high rates of virological failure in several studied combination regimens for the treatment of HIV-1 infection. |
Co-administration of tenofovir disoproxil fumarate with didanosine is not recommended. (See section "Special warnings and precautions for use"). |
| Adefovir dipivoxil |
AUC: ↔ Cmax: ↔ |
Tenofovir disoproxil fumarate should not be administered concurrently with adefovir dipivoxil (see section "Special warnings and precautions for use"). |
| Entecavir |
AUC: ↔ Cmax: ↔ |
No clinically significant pharmacokinetic interactions were observed when tenofovir disoproxil fumarate was administered with entecavir. |
| Antiviral agents for hepatitis C |
||
| Ledipasvir/sofosbuvir (90 mg/400 mg q.d.) + atazanavir/ritonavir (300 mg q.d./100 mg q.d.) + emtricitabine/tenofovir disoproxil fumarate (200 mg/300 mg q.d.)1 |
Ledipasvir: AUC: ↑ 96 % Cmax: ↑ 68 % Cmin: ↑ 118 % Sofosbuvir: AUC: ↔ Cmax: ↔ GS-3310072: AUC: ↔ Cmax: ↔ Cmin: ↑ 42 % Atazanavir: AUC: ↔ Cmax: ↔ Cmin: ↑ 63 % Ritonavir: AUC: ↔ Cmax: ↔ Cmin: ↑ 45 % Emtricitabine: AUC: ↔ Cmax: ↔ Cmin: ↔ Tenofovir: AUC: ↔ Cmax: ↑ 47 % Cmin: ↑ 47 % |
Elevated plasma concentrations of tenofovir resulting from co-administration of tenofovir disoproxil fumarate, ledipasvir/sofosbuvir, and atazanavir/ritonavir may enhance adverse reactions associated with tenofovir disoproxil fumarate, including renal disorders. The safety of tenofovir disoproxil fumarate when used with ledipasvir/sofosbuvir and a pharmacokinetic enhancer (e.g., ritonavir or cobicistat) has not been established. This combination should be used with frequent monitoring of renal function if alternative treatment options are not available (see section "Special warnings and precautions for use"). |
| Ledipasvir/sofosbuvir (90 mg/400 mg q.d.) + darunavir/ritonavir (800 mg q.d./100 mg q.d.) + emtricitabine/tenofovir disoproxil fumarate (200 mg/300 mg q.d.)1 |
Ledipasvir: AUC: ↔ Cmax: ↔ Cmin: ↔ Sofosbuvir: AUC: ↓ 27 % Cmax: ↓ 37 % GS-3310072: AUC: ↔ Cmax: ↔ Cmin: ↔ Darunavir: AUC: ↔ Cmax: ↔ Cmin: ↔ Ritonavir: AUC: ↔ Cmax: ↔ Cmin: ↑ 48 % Emtricitabine: AUC: ↔ Cmax: ↔ Cmin: ↔ Tenofovir: AUC: ↑ 50 % Cmax: ↑ 64 % Cmin: ↑ 59 % |
Elevated plasma concentrations of tenofovir resulting from co-administration of tenofovir disoproxil fumarate, ledipasvir/sofosbuvir, and darunavir/ritonavir may enhance adverse reactions associated with tenofovir disoproxil fumarate, including renal disorders. The safety of tenofovir disoproxil fumarate when used with ledipasvir/sofosbuvir and a pharmacokinetic enhancer (e.g., ritonavir or cobicistat) has not been established. This combination should be used with frequent monitoring of renal function if alternative treatment options are not available (see section "Special warnings and precautions for use"). |
| Ledipasvir/sofosbuvir (90 mg/400 mg q.d.) + efavirenz/emtricitabine/ tenofovir disoproxil fumarate (600 mg/200 mg/300 mg q.d.) |
Ledipasvir: AUC: ↓ 34 % Cmax: ↓ 34 % Cmin: ↓ 34 % Sofosbuvir: AUC: ↔ Cmax: ↔ GS-3310072: AUC: ↔ Cmax: ↔ Cmin: ↔ Efavirenz: AUC: ↔ Cmax: ↔ Cmin: ↔ Emtricitabine: AUC: ↔ Cmax: ↔ Cmin: ↔ Tenofovir: AUC: ↑ 98 % Cmax: ↑ 79 % Cmin: ↑ 163 % |
Dose adjustment is not recommended. Increased tenofovir dosage may enhance adverse reactions associated with tenofovir disoproxil fumarate, including renal impairment. Renal function should be closely monitored (see section "Special warnings and precautions for use"). |
| Ledipasvir/sofosbuvir (90 mg/400 mg q.d.) + emtricitabine/rilpivirine/ tenofovir disoproxil fumarate (200 mg/25 mg/300 mg q.d.) |
Ledipasvir: AUC: ↔ Cmax: ↔ Cmin: ↔ Sofosbuvir: AUC: ↔ Cmax: ↔ GS-3310072: AUC: ↔ Cmax: ↔ Cmin: ↔ Emtricitabine: AUC: ↔ Cmax: ↔ Cmin: ↔ Rilpivirine: AUC: ↔ Cmax: ↔ Cmin: ↔ Tenofovir: AUC: ↑ 40 % Cmax: ↔ Cmin: ↑ 91 % |
Dose adjustment is not recommended. Increased tenofovir dosage may enhance adverse reactions associated with tenofovir disoproxil fumarate, including renal impairment. Renal function should be closely monitored (see section "Special warnings and precautions for use"). |
| Ledipasvir/sofosbuvir (90 mg/400 mg q.d.) + dolutegravir (50 mg q.d.) + emtricitabine/tenofovir disoproxil fumarate (200 mg/300 mg q.d.) |
Sofosbuvir: AUC: ↔ Cmax: ↔ GS-3310072: AUC: ↔ Cmax: ↔ Cmin: ↔ Ledipasvir: AUC: ↔ Cmax: ↔ Cmin: ↔ Dolutegravir: AUC: ↔ Cmax: ↔ Cmin: ↔ Emtricitabine: AUC: ↔ Cmax: ↔ Cmin: ↔ Tenofovir: AUC: ↑ 65 % Cmax: ↑ 61 % Cmin: ↑ 115 % |
Dose adjustment is not recommended. Increased tenofovir dosage may enhance adverse reactions associated with tenofovir disoproxil fumarate, including renal impairment. Renal function should be closely monitored (see section "Special warnings and precautions for use"). |
| Sofosbuvir/velpatasvir (400 mg/100 mg q.d.) + atazanavir/ritonavir (300 mg q.d./100 mg q.d.) + emtricitabine/tenofovir disoproxil fumarate (200 mg/300 mg q.d.)1 |
Sofosbuvir: AUC: ↔ Cmax: ↔ GS-3310072: AUC: ↔ Cmax: ↔ Cmin: ↑ 42 % Velpatasvir: AUC: ↑ 142 % Cmax: ↑ 55 % Cmin: ↑ 301 % Atazanavir: AUC: ↔ Cmax: ↔ Cmin: ↑ 39 % Ritonavir: AUC: ↔ Cmax: ↔ Cmin: ↑ 29 % Emtricitabine: AUC: ↔ Cmax: ↔ Cmin: ↔ Tenofovir: AUC: ↔ Cmax: ↑ 55 % Cmin: ↑ 39 % |
Elevated plasma concentrations of tenofovir resulting from co-administration of tenofovir disoproxil fumarate, sofosbuvir/velpatasvir, and atazanavir/ritonavir may enhance adverse reactions associated with tenofovir disoproxil fumarate, including renal disorders. The safety of tenofovir disoproxil fumarate when used with sofosbuvir/velpatasvir and a pharmacokinetic enhancer (e.g., ritonavir or cobicistat) has not been established. This combination should be used with frequent monitoring of renal function (see section "Special warnings and precautions for use"). |
| Sofosbuvir/velpatasvir (400 mg/100 mg q.d.) + darunavir/ritonavir (800 mg q.d./100 mg q.d.) + emtricitabine/tenofovir disoproxil fumarate (200 mg/300 mg q.d.)1 |
Sofosbuvir: AUC: ↓ 28 % Cmax: ↓ 38 % GS-3310072: AUC: ↔ Cmax: ↔ Cmin: ↔ Velpatasvir: AUC: ↔ Cmax: ↓ 24 % Cmin: ↔ Darunavir: AUC: ↔ Cmax: ↔ Cmin: ↔ Ritonavir: AUC: ↔ Cmax: ↔ Cmin: ↔ Emtricitabine: AUC: ↔ Cmax: ↔ Cmin: ↔ Tenofovir: AUC: ↑ 39 % Cmax: ↑ 55 % Cmin: ↑ 52 % |
Elevated plasma concentrations of tenofovir resulting from co-administration of tenofovir disoproxil fumarate, sofosbuvir/velpatasvir, and darunavir/ritonavir may enhance adverse reactions associated with tenofovir disoproxil fumarate, including renal disorders. The safety of tenofovir disoproxil fumarate when used with sofosbuvir/velpatasvir and a pharmacokinetic enhancer (e.g., ritonavir or cobicistat) has not been established. This combination should be used with frequent monitoring of renal function (see section "Special warnings and precautions for use"). |
| Sofosbuvir/velpatasvir (400 mg/100 mg q.d.) + lopinavir/ritonavir (800 mg/200 mg q.d.) + emtricitabine/tenofovir disoproxil fumarate (200 mg/300 mg q.d.) |
Sofosbuvir: AUC: ↓ 29 % Cmax: ↓ 41 % GS-3310072: AUC: ↔ Cmax: ↔ Cmin: ↔ Velpatasvir: AUC: ↔ Cmax: ↓ 30 % Cmin: ↑ 63 % Lopinavir: AUC: ↔ Cmax: ↔ Cmin: ↔ Ritonavir: AUC: ↔ Cmax: ↔ Cmin: ↔ Emtricitabine: AUC: ↔ Cmax: ↔ Cmin: ↔ Tenofovir: AUC: ↔ Cmax: ↑ 42 % Cmin: ↔ |
Elevated plasma concentrations of tenofovir resulting from co-administration of tenofovir disoproxil fumarate, sofosbuvir/velpatasvir, and lopinavir/ritonavir may enhance adverse reactions associated with tenofovir disoproxil fumarate, including renal disorders. The safety of tenofovir disoproxil fumarate when used with sofosbuvir/velpatasvir and a pharmacokinetic enhancer (e.g., ritonavir or cobicistat) has not been established. This combination should be used with frequent monitoring of renal function (see section "Special warnings and precautions for use"). |
| Sofosbuvir/velpatasvir (400 mg/100 mg q.d.) + raltegravir (400 mg b.i.d.) + emtricitabine/tenofovir disoproxil fumarate (200 mg/300 mg q.d.) |
Sofosbuvir: AUC: ↔ Cmax: ↔ GS-3310072: AUC: ↔ Cmax: ↔ Cmin: ↔ Velpatasvir: AUC: ↔ Cmax: ↔ Cmin: ↔ Raltegravir: AUC: ↔ Cmax: ↔ Cmin: ↓ 21 % Emtricitabine: AUC: ↔ Cmax: ↔ Cmin: ↔ Tenofovir: AUC: ↑ 40 % Cmax: ↑ 46 % Cmin: ↑ 70 % |
Dose adjustment is not recommended. Increased tenofovir dosage may enhance adverse reactions associated with tenofovir disoproxil fumarate, including renal impairment. Renal function should be closely monitored (see section "Special warnings and precautions for use"). |
| Sofosbuvir/velpatasvir/ voxilaprevir (400 mg/100 mg/ 100 mg + 100 mg q.d.)3 + darunavir (800 mg q.d.) + ritonavir (100 mg q.d.) + emtricitabine/tenofovir disoproxil fumarate (200 mg/300 mg q.d.) |
Sofosbuvir: AUC: ↔ Cmax: ↑ 30 % Cmin: N/A GS-3310072: AUC: ↔ Cmax: ↔ Cmin: N/A Velpatasvir: AUC: ↔ Cmax: ↔ Cmin: ↔ Voxilaprevir: AUC: ↑ 143 % Cmax: ↑ 72 % Cmin: ↑ 300 % Darunavir: AUC: ↔ Cmax: ↔ Cmin: ↓ 34 % Ritonavir: AUC: ↑ 45 % Cmax: ↑ 60 % Cmin: ↔ Emtricitabine: AUC: ↔ Cmax: ↔ Cmin: ↔ Tenofovir: AUC: ↑ 39 % Cmax: ↑ 48 % Cmin: ↑ 47 % |
Elevated plasma concentrations of tenofovir resulting from co-administration of tenofovir disoproxil fumarate, sofosbuvir/velpatasvir/voxilaprevir, and darunavir/ritonavir may enhance adverse reactions associated with tenofovir disoproxil fumarate, including renal disorders. The safety of tenofovir disoproxil fumarate when used with sofosbuvir/velpatasvir/voxilaprevir and a pharmacokinetic enhancer (e.g., ritonavir or cobicistat) has not been established. This combination should be used with frequent monitoring of renal function (see section "Special warnings and precautions for use"). |
| Sofosbuvir/velpatasvir (400 mg/100 mg q.d.) + efavirenz/emtricitabine/ tenofovir disoproxil fumarate (600 mg/200 mg/300 mg q.d.) |
Sofosbuvir: AUC: ↔ Cmax: ↑ 38 % GS-3310072: AUC: ↔ Cmax: ↔ Cmin: ↔ Velpatasvir: AUC: ↓ 53 % Cmax: ↓ 47 % Cmin: ↓ 57 % Efavirenz: AUC: ↔ Cmax: ↔ Cmin: ↔ Emtricitabine: AUC: ↔ Cmax: ↔ Cmin: ↔ Tenofovir: AUC: ↑ 81 % Cmax: ↑ 77 % Cmin: ↑ 121 % |
Concomitant administration of sofosbuvir/velpatasvir with efavirenz is expected to reduce plasma concentrations of velpatasvir. Concomitant administration of sofosbuvir/velpatasvir as part of treatment regimens containing efavirenz is not recommended. |
| Sofosbuvir/velpatasvir (400 mg/100 mg q.d.) + emtricitabine/rilpivirine /tenofovir disoproxil fumarate (200 mg/25 mg/300 mg q.d.) |
Sofosbuvir: AUC: ↔ Cmax: ↔ GS-3310072: AUC: ↔ Cmax: ↔ Cmin: ↔ Velpatasvir: AUC: ↔ Cmax: ↔ Cmin: ↔ Emtricitabine: AUC: ↔ Cmax: ↔ Cmin: ↔ Rilpivirine: AUC: ↔ Cmax: ↔ Cmin: ↔ Tenofovir: AUC: ↑ 40 % Cmax: ↑ 44 % Cmin: ↑ 84 % |
Dose adjustment is not recommended. Increased tenofovir dosage may enhance adverse reactions associated with tenofovir disoproxil fumarate, including renal impairment. Renal function should be closely monitored (see section "Special warnings and precautions for use"). |
| Sofosbuvir (400 mg q.d.) + efavirenz/emtricitabine /tenofovir disoproxil fumarate (600 mg/200 mg/300 mg q.d.) |
Sofosbuvir: AUC: ↔ Cmax: ↓ 19 % GS-3310072: AUC: ↔ Cmax: ↓ 23 % Efavirenz: AUC: ↔ Cmax: ↔ Cmin: ↔ Emtricitabine: AUC: ↔ Cmax: ↔ Cmin: ↔ Tenofovir: AUC: ↔ Cmax: ↑ 25 % Cmin: ↔ |
Dose adjustment is not required. |
1 Data obtained with concomitant use of ledipasvir/sofosbuvir. Sequential administration (with a 12-hour interval) 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
Before initiating tenofovir disoproxil fumarate therapy, an HIV antibody test should be offered to all HBV-infected patients (see sections below "HIV-1 and hepatitis B co-infection").
HIV-1: Since effective viral suppression by antiretroviral therapy with tenofovir disoproxil fumarate has not been proven to substantially reduce the risk of sexual transmission, residual risk cannot be excluded. Preventive measures to avoid transmission should be taken according to national recommendations.
Chronic hepatitis B: Patients should be informed that there is no evidence that tenofovir disoproxil fumarate prevents the risk of transmission to others via sexual contact or blood exposure. Appropriate preventive measures should continue to be used.
Concomitant use with other medicinal products.
- Tenofovir disoproxil fumarate should not be used with other medicinal products containing tenofovir disoproxil fumarate or tenofovir alafenamide.
- Tenofovir disoproxil fumarate should not be used concomitantly with adefovir dipivoxil.
- Concomitant use of tenofovir disoproxil fumarate and didanosine is not recommended. Concomitant use of tenofovir disoproxil fumarate and didanosine results in a 40–60% increase in systemic exposure to didanosine, increasing the risk of didanosine-related adverse events. Rare, sometimes fatal cases of pancreatitis and lactic acidosis have been reported. Concomitant use of tenofovir disoproxil fumarate and didanosine at a dose of 400 mg daily has been associated with significant decreases in CD4 cell count, possibly due to intracellular interaction increasing phosphorylated (i.e. active) didanosine. A reduced dose of 250 mg didanosine administered with tenofovir disoproxil fumarate therapy has been associated with reports of high rates of virological treatment failure in several combination regimens studied for treatment of HIV-1 infection.
Triple nucleoside/nucleotide therapy. Reports have indicated a high frequency of early virological treatment 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
Effect on renal function. 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 during clinical use of tenofovir disoproxil fumarate (see section "Adverse reactions").
Monitoring of renal function. Calculation of creatinine clearance is recommended in all patients before starting tenofovir disoproxil fumarate therapy, and renal function (creatinine clearance and serum phosphate levels) should be checked 2–4 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 fall below 1.5 mg/dL (0.48 mmol/L) or creatinine clearance decreases to < 50 mL/min in any patient receiving tenofovir disoproxil fumarate, renal function should be re-evaluated within one week, including measurement of blood glucose, blood potassium, and urine glucose concentration (see section "Adverse reactions", proximal tubulopathy). Discontinuation of tenofovir disoproxil fumarate therapy should also be considered in patients whose creatinine clearance decreases to < 50 mL/min or whose serum phosphate levels fall 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 or recent use of nephrotoxic medicinal products (e.g., aminoglycosides, amphotericin B, foscarnet, ganciclovir, pentamidine, vancomycin, cidofovir, and interleukin-2) with tenofovir disoproxil fumarate 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 nonsteroidal 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. Renal function should be appropriately monitored when tenofovir disoproxil fumarate is used concomitantly with NSAIDs.
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 a boosted protease inhibitor 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 via the same route—i.e., through the kidneys, 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 via the same renal pathway, including hOAT 1 and 3 or MRP 4 transporters, may be altered when administered concomitantly. Concomitant use of medicinal products eliminated via 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. Renal safety of tenofovir disoproxil fumarate has been studied to a very limited extent in adult patients with impaired renal function (creatinine clearance < 80 mL/min).
Adult patients with creatinine clearance < 50 mL/min, including patients on hemodialysis.
Safety data on the use of tenofovir disoproxil fumarate in patients with renal impairment are limited. Therefore, tenofovir disoproxil fumarate should be prescribed only if 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 hemodialysis. If no alternative treatment is available, the dosing interval should be adjusted and renal function carefully monitored (see sections "Pharmacokinetics" and "Posology and method of administration").
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 fumarate-induced proximal renal tubulopathy (see section "Adverse reactions").
Decreases in bone mineral density (BMD) have been observed during clinical trials of up to 144 weeks in HIV- or HBV-infected patients receiving tenofovir disoproxil fumarate (see sections "Pharmacodynamics" and "Adverse reactions"). These BMD decreases generally improve after discontinuation of therapy.
In other studies, the most pronounced BMD decreases were observed in patients receiving tenofovir disoproxil fumarate as part of a regimen containing a boosted protease inhibitor.
Overall, considering the bone abnormalities associated with tenofovir disoproxil fumarate and the limited long-term data on its impact on bone health and fracture risk, alternative treatment regimens should be considered for patients with osteoporosis or a history of bone fractures.
Appropriate consultation should be obtained if bone abnormalities are suspected or identified.
Renal and bone effects in the paediatric population.
There are uncertainties regarding the long-term effects of renal and bone toxicity. Additionally, the reversibility of renal toxicity cannot be fully established. Therefore, a multidisciplinary approach is recommended to adequately assess the individual benefit-risk ratio of treatment, make decisions regarding appropriate monitoring during therapy (including decisions on treatment discontinuation), and consider the need for dietary supplements.
Monitoring of renal function
Renal function (serum creatinine clearance and phosphate) should be evaluated before starting treatment and monitored during therapy as in adults (see above).
Treatment of renal disorders
If serum phosphate levels are confirmed below 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 concentration (see section "Adverse reactions", proximal tubulopathy). In case of suspected or confirmed renal abnormalities, consultation with a nephrologist is required to consider the possibility of interrupting tenofovir disoproxil fumarate therapy. 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 failure.
Tenofovir disoproxil fumarate is not recommended for children with renal failure (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 failure during tenofovir disoproxil fumarate therapy.
Bone effects
Tenofovir disoproxil fumarate 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 currently unknown (see section "Pharmacodynamics").
If bone abnormalities are identified or suspected in children, consultation with an endocrinologist and/or nephrologist is required.
Liver disease. Safety and efficacy data 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 (CPT) 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 transient increases 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 accompany increases in 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 generally associated with increases in HBV DNA, 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 developing 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 such 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. Plasma concentrations of tenofovir are increased when tenofovir disoproxil fumarate is used with ledipasvir/sofosbuvir, sofosbuvir/velpatasvir, or sofosbuvir/velpatasvir/voxilaprevir, especially when used together 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 metabolic parameters. Increases in body weight and levels of lipids and glucose in blood may occur during antiretroviral therapy in patients. These changes may be partly associated with both therapy and lifestyle. Regarding lipids, there is some evidence of treatment impact in certain cases, whereas for weight gain, there is no substantial evidence linking it to any specific treatment. Monitoring of blood lipids and glucose should follow established HIV treatment guidelines. Lipid disorders should be clinically managed.
Mitochondrial dysfunction following in utero exposure.
Nucleoside and nucleotide analogues may cause mitochondrial damage of varying degrees, particularly associated with stavudine, didanosine, and zidovudine. Cases of mitochondrial dysfunction have been reported in HIV-negative children exposed to nucleoside analogues in utero and/or postnatally. This primarily concerns treatment regimens containing zidovudine. The main adverse events reported were haematological disorders (anaemia, neutropenia) and metabolic disturbances (hyperlactataemia, hyperlipasaemia). These events were often transient. Rarely, delayed-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 in any child exposed in utero to nucleoside or nucleotide analogues associated with serious clinical disorders of unknown aetiology, particularly neurological disorders. These findings do not affect current national recommendations for 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, potentially causing serious clinical conditions or worsening of symptoms. Such reactions typically occur within the first few weeks or months of starting cART. Typical examples include cytomegalovirus retinitis, generalized and/or focal mycobacterial infections, and Pneumocystis jirovecii pneumonia. Any inflammatory symptoms should be evaluated and treatment initiated if necessary.
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 starting 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 seek medical advice if they experience joint pain, joint stiffness, or difficulty moving.
Older patients.
Tenofovir disoproxil has not been studied in patients over 65 years of age. Older patients often have reduced renal function; therefore, caution should be exercised when prescribing tenofovir disoproxil fumarate to these patients.
Tenofovir disoproxil fumarate 300 mg film-coated tablets contain lactose monohydrate. Therefore, patients with rare hereditary problems of galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption should not take this medicine.
Use during pregnancy or breastfeeding.
Pregnancy
A large amount of data on use in pregnant women (over 1000 completed pregnancies) indicates no malformations or embryo/fetal toxicity associated with tenofovir disoproxil fumarate. Animal studies have shown no toxic effect on reproductive function. Tenofovir disoproxil fumarate may be used during pregnancy if necessary.
Breastfeeding
Tenofovir has been found to pass into human breast milk. There is insufficient information on the effects of tenofovir on newborns/infants. Therefore, tenofovir disoproxil fumarate should not be used during breastfeeding.
In general, HIV- and HBV-infected women are advised not to breastfeed in order to avoid transmission of HIV or HBV infection to the child.
Fertility
Clinical data on the effect of tenofovir disoproxil fumarate on fertility are limited. Animal studies have shown 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
Adults
The recommended dose for the treatment of HIV or chronic hepatitis B is 1 tablet once daily, taken orally with food.
Chronic hepatitis B. The optimal duration of treatment is unknown. Criteria for discontinuation of treatment may include:
- Treatment of patients who are hepatitis B e antigen (HBeAg)-positive without cirrhosis should last for at least 6–12 months after confirmed HBe seroconversion (loss of hepatitis B virus antigens and HBV DNA with detection of anti-HBe) or until HBs seroconversion, or until loss of response (see section "Special Warnings and Precautions for Use"). After stopping treatment, alanine aminotransferase (ALT) levels and serum HBV DNA should be monitored regularly to detect any late virological relapses;
- Treatment of patients who are hepatitis B e antigen (HBeAg)-negative without cirrhosis should last for at least until HBs seroconversion or until loss of response. For prolonged treatment lasting longer than 2 years, periodic re-evaluation of treatment is recommended to confirm that the chosen therapy remains appropriate for the patient.
Children
HIV-1: For adolescents aged 12 to < 18 years with body weight ≥ 35 kg, the recommended dose of tenofovir disoproxil fumarate is 1 tablet once daily, taken orally with food (see sections "Adverse Reactions" and "Pharmacodynamics").
Chronic hepatitis B: For adolescents aged 12 to < 18 years with body weight ≥ 35 kg, the recommended dose of tenofovir disoproxil fumarate is 1 tablet once daily, taken orally with food (see sections "Adverse Reactions" and "Pharmacodynamics"). The optimal duration of treatment is currently unknown.
Missed Dose
If a patient misses a dose of tenofovir disoproxil fumarate and less than 12 hours have passed since the time the dose was due, the patient should take the missed dose with food as soon as possible, then resume the normal dosing schedule. If a patient misses a dose of tenofovir disoproxil fumarate and more than 12 hours have passed since the time the dose was due (i.e., it is almost time for the next dose), the patient should not take the missed dose but should continue with the next scheduled dose.
If vomiting occurs within 1 hour after taking tenofovir disoproxil fumarate, the patient should take another tablet. If vomiting occurs more than 1 hour after taking tenofovir disoproxil fumarate, there is no need to take another tablet.
Special Patient Populations
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 by the kidneys; therefore, patients with renal dysfunction are exposed to higher levels of tenofovir.
Adults. Data on the safety and efficacy of tenofovir disoproxil fumarate in patients with moderate and severe renal impairment (creatinine clearance < 50 mL/min) are limited. 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 patients with creatinine clearance < 50 mL/min, including those undergoing hemodialysis.
Mild renal impairment (creatinine clearance 50–80 mL/min). Limited clinical trial data support the use of tenofovir disoproxil fumarate once daily in patients with mild renal impairment.
Moderate renal impairment (creatinine clearance 30–49 mL/min). Administration of 1 tablet of tenofovir disoproxil fumarate every 48 hours 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 confirmed in clinical trials. 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 unavailability of tablets with different active ingredient content; therefore, use of the drug in these patient groups is not recommended. If no alternative therapy is available, extended dosing intervals may be considered as follows:
- In patients with severe renal impairment: 1 tablet of tenofovir disoproxil fumarate every 72–96 hours (twice weekly);
- In patients on hemodialysis: 1 tablet of tenofovir disoproxil fumarate once every 7 days after completion of a hemodialysis session (typically once weekly, assuming 3 hemodialysis sessions per week, each lasting approximately 4 hours, or after 12 hours of cumulative hemodialysis).
These proposed dosing interval adjustments have not been confirmed in clinical trials. There are concerns that prolonged dosing intervals of tenofovir disoproxil fumarate film-coated tablets 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 dosage adjustment is necessary 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, who discontinue tenofovir disoproxil fumarate should be closely monitored for signs of hepatitis flare (see section "Special Warnings and Precautions for Use").
Method of Administration
Tenofovir disoproxil fumarate tablets should be taken once daily, orally, with food.
If patients have difficulty swallowing, tenofovir disoproxil fumarate tablets may be crushed and mixed with approximately 100 mL of water, orange juice, or grape juice and taken 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 case 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 tenofovir clearance of 134 mL/min. Removal of tenofovir by peritoneal dialysis has not been studied.
Adverse Reactions
Summary of Safety Profile
HIV-1 and Hepatitis B. Renal adverse events, including renal impairment, renal failure, and proximal renal tubulopathy (including Fanconi syndrome), have been reported rarely in patients receiving tenofovir disoproxil fumarate. These events have sometimes led to bone abnormalities (rarely fractures). Monitoring of renal function is recommended for patients receiving tenofovir disoproxil fumarate (see section "Special Warnings and Precautions for Use").
HIV-1. Adverse reactions during treatment with tenofovir disoproxil fumarate in combination with other antiretroviral agents are expected in approximately one-third of patients. These are usually mild to moderate gastrointestinal events. Approximately 1% of patients receiving tenofovir disoproxil fumarate discontinue treatment due to gastrointestinal adverse reactions.
Concomitant administration of tenofovir disoproxil fumarate and didanosine is not recommended, as it increases the risk of adverse reactions (see section "Interaction with Other Medicinal Products and Other Forms of Interaction"). Pancreatitis and lactic acidosis, sometimes fatal, have been reported rarely (see section "Special Warnings and Precautions for Use").
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 commonly reported adverse reaction to 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 surveillance. All adverse reactions are listed in Table 2.
HIV-1 Clinical Trials. Assessment of adverse reactions in HIV-1 clinical trials is based on data 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, as well as data from a double-blind, controlled comparative trial in which 600 treatment-naïve patients received 245 mg tenofovir disoproxil (as fumarate) (n = 299) or stavudine (n = 301) in combination with lamivudine and efavirenz for 144 weeks.
Hepatitis B Clinical Trials. Assessment of adverse reactions in hepatitis B clinical trials is primarily based on results from two double-blind, controlled comparative studies in which 641 patients with chronic hepatitis B and compensated liver disease received either 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. After 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) within the first 4 weeks of treatment, the annual decline in renal function compared to baseline 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 patients received tenofovir disoproxil fumarate (n = 45), emtricitabine plus 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 serum creatinine increases ≥ 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. Subjects with higher baseline Child–Pugh–Turcotte (CPT) scores were reported to have a higher risk of 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 study in which 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 grouping, adverse events are presented in order of decreasing severity. Adverse reactions by frequency are defined as: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1000 to < 1/100), and rare (≥ 1/10,000 to < 1/1000).
Summary table of adverse reactions associated with tenofovir disoproxil fumarate based on clinical trial and post-marketing data
Table 2
| Organ system classes and frequency |
Adverse reactions |
| Metabolism and nutrition disorders |
|
| Very common |
Hypophosphatemia1 |
| Uncommon |
Hypokalemia1 |
| Rare |
Lactic acidosis |
| Nervous system disorders |
|
| Very common |
Dizziness |
| Common |
Headache |
| Gastrointestinal disorders |
|
| Very common |
Diarrhea, vomiting, nausea |
| Common |
Abdominal pain, bloating, flatulence |
| Uncommon |
Pancreatitis |
| Hepatobiliary disorders |
|
| Common |
Elevated transaminase levels |
| Rare |
Fatty degeneration of the liver, hepatitis |
| Skin and subcutaneous tissue disorders |
|
| Very common |
Rash |
| Rare |
Angioneurotic edema |
| Musculoskeletal and connective tissue disorders |
|
| Common |
Decreased bone mineral density3 |
| Uncommon |
Rhabdomyolysis1, muscle weakness1 |
| Rare |
Osteomalacia (manifested as bone pain and infrequently as a cause of fractures)1, 2, myopathy1 |
| Renal and urinary disorders |
|
| Uncommon |
Elevated creatinine, proximal renal tubulopathy (including Fanconi syndrome) |
| Rare |
Acute renal failure, renal failure, acute tubular necrosis, nephritis (including acute interstitial nephritis)2, nephrogenic diabetes insipidus |
| General disorders and administration site conditions |
|
| Very common |
Asthenia |
| Common |
Fatigue |
1 A side effect 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 condition.
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 determined by statistical calculations based on 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 collected during various clinical trials of tenofovir disoproxil fumarate in HBV-infected patients. See also sections “Pharmacodynamics” and “Special precautions for use”.
Description of selected adverse reactions
HIV-1 and Hepatitis B
Renal impairment. Since the drug Tenofovir disoproxil fumarate may lead to kidney dysfunction, monitoring of renal function is recommended (see sections “Special precautions for use” and “Summary of safety profile”). Proximal renal tubulopathy was generally reversible or showed improvement after discontinuation of tenofovir disoproxil fumarate. However, in some patients, the decline in creatinine clearance did not completely resolve despite discontinuation of tenofovir disoproxil fumarate. Patients at risk of renal function impairment (e.g., patients with baseline risk factors for renal disorders, 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 precautions for use”).
HIV-1
Interaction with didanosine. Concomitant administration of tenofovir disoproxil fumarate and didanosine is not recommended, as it leads to a 40–60% increase in systemic exposure to didanosine, thereby increasing the risk of didanosine-related adverse reactions (see section “Interaction with other medicinal products”). Pancreatitis and lactic acidosis, sometimes fatal, have been rarely reported.
Metabolic abnormalities. Body weight, as well as blood lipid and glucose levels, may increase during antiretroviral therapy (see section “Special 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 varied widely and these events may occur many months after initiation of treatment (see section “Special precautions for use”).
Osteonecrosis. Cases of osteonecrosis have been reported in patients with generally recognized risk factors, advanced HIV disease, or long-term exposure to cART. The frequency of occurrence is unknown (see section “Special precautions for use”).
Hepatitis B
Hepatitis flare during treatment. In clinical trials involving nucleoside-naïve patients, ALT elevations exceeding 10 times the upper limit of normal and doubling of baseline levels were observed in 2.6% of patients receiving tenofovir disoproxil fumarate treatment. ALT elevations occurred at a median of 8 weeks and were managed with continued treatment. In most cases, these ALT elevations were preceded or accompanied by a ≥ 2 log10 copies/mL reduction in viral load. Monitoring of liver function is recommended during treatment (see section “Special 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 precautions for use”).
Use in adolescents
HIV-1
Adverse reactions observed in adolescent patients receiving tenofovir disoproxil fumarate treatment were consistent with those observed in adults during clinical trials of tenofovir disoproxil fumarate (see sections “Pharmacodynamics” and “Summary table of adverse reactions”).
Decreases in BMD Z-scores have been reported in pediatric patients. In HIV-1-infected adolescents, BMD Z-scores observed during tenofovir disoproxil fumarate treatment were lower than those observed with placebo. In HIV-1-infected children, BMD Z-scores observed in patients who switched to tenofovir disoproxil fumarate were lower compared to those continuing stavudine or zidovudine (see sections “Pharmacodynamics” and “Special precautions for use”).
Chronic Hepatitis B
Adverse reactions observed in adolescent patients receiving tenofovir disoproxil fumarate treatment were consistent with those observed in adults during clinical trials of tenofovir disoproxil fumarate (see sections “Summary table of adverse reactions” and “Pharmacodynamics”).
Decreases in BMD were observed in HBV-infected adolescents. The BMD Z-score observed in patients receiving tenofovir disoproxil fumarate treatment was comparable to that observed in patients receiving placebo (see sections “Special precautions for use” and “Pharmacodynamics”).
Other special patient groups
Elderly patients. The effect of tenofovir disoproxil fumarate in patients aged over 65 years has not been studied. 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 precautions for use”).
Patients with renal impairment. Since tenofovir disoproxil fumarate may lead to nephrotoxicity, renal function should be monitored in all patients with renal impairment who are taking Tenofovir disoproxil fumarate (see sections “Dosage and administration”, “Special 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 precautions for use”).
If adverse reactions occur, consult a physician.
Shelf life. 3 years.
Storage conditions. Store in the original packaging at a temperature not exceeding 30 °C, in a place inaccessible to children.
Packaging. 30 tablets in a container; 1 container in a cardboard box.
Prescription status. Prescription only.
Manufacturer. Hetero Labs Limited.
Manufacturer’s address and place of business.
Unit III, Formulation Plot No 22 – 110 IDA, Jeedimetla, Hyderabad, 500 055 Telangana, India.