Tenofovir disoproxil fumarate
Ukraine
Table of Contents
INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT TENOFOVIR DISOPROXIL FUMARATE
Composition:
Active substance: tenofovir disoproxil;
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 White (Y-1-7000).
Pharmaceutical form. Film-coated tablets.
Main physicochemical properties: white, round, biconvex film-coated tablets, with "TDF" debossed on one side and smooth 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 substance tenofovir, which is a nucleoside monophosphate analog (nucleotide). 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 deoxyribonucleotide substrate for direct binding and by causing DNA 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 affect mitochondrial DNA synthesis or lactate production.
Data Regarding HIV Virus.
Anti-HIV 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, and against HIVBaL in primary monocytes/macrophages. 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. Tenofovir disoproxil fumarate should be avoided in patients previously treated with antiretroviral agents who harbor 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).
Anti-HBV Activity 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 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 resistance-associated mutations to adefovir, rtA181V and rtN236T, 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 ranging from 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 those who had not received prior therapy, patients previously treated with lamivudine, adefovir, or dipivoxil, and patients with baseline resistance mutations to lamivudine and/or adefovir dipivoxil. Efficacy has also been 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 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, 3324 (41.2%) ng×h/mL, and 64.4 (39.4%) ng/mL, respectively. Maximum tenofovir concentration in plasma occurs 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 following a high-fat meal, median Cmax in plasma 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 was less than 0.7% and 7.2%, respectively, over a concentration range of tenofovir from 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 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 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 is approximately 230 mL/h/kg (approximately 300 mL/min); renal clearance is approximately 160 mL/h/kg (approximately 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 involving elderly patients (aged 65 years and older) have not been conducted.
Sex
Limited pharmacokinetic data in women suggest that sex has no significant effect.
Ethnicity
Pharmacokinetics in different ethnic groups has 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. Mean (± SD) Cmax was 0.38 ± 0.13 µg/mL and AUCtau was 3.39 ± 1.22 µg×h/mL. Tenofovir exposure in adolescent patients receiving 245 mg tenofovir disoproxil (as fumarate) daily was similar to that in adult patients receiving 245 mg tenofovir disoproxil (as fumarate) daily.
Chronic Hepatitis B. The effect of tenofovir at steady state in HBV-infected patients (aged 12 to < 18 years) receiving a single oral dose of 245 mg tenofovir disoproxil (as fumarate) was similar to that in adults receiving a single oral dose of 245 mg tenofovir disoproxil (as fumarate).
Pharmacological studies involving children aged 12 years and older, including children with renal impairment, have not been conducted.
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, categorized according to baseline creatinine clearance (CrCl) (normal renal function: CrCl > 80 mL/min; mild impairment: CrCl 50–79 mL/min; moderate impairment: CrCl 30–49 mL/min; severe impairment: CrCl 10–29 mL/min). Compared to patients with normal renal function (CrCl > 80 mL/min), mean exposure (% CV) of tenofovir increased from 2185 (12%) ng×h/mL to 3064 (30%) ng×h/mL, 6009 (42%) ng×h/mL, and 15985 (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 significantly increased over 48 hours between dialysis sessions, reaching a mean Cmax of 1032 ng/mL and a mean AUC0–48h of 42857 ng×h/mL.
It is recommended that the dosing interval of tenofovir disoproxil 245 mg (as fumarate) be adjusted in patients with CrCl < 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 insufficiency has not been studied. There are no data on dosage recommendations (see sections "Special Warnings and Precautions for Use" and "Dosage and Administration").
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 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–∞ of tenofovir were 223 (34.8%) ng/mL and 2050 (50.8%) ng×h/mL, respectively, in individuals without hepatic impairment, 289 (46.0%) ng/mL and 2310 (43.5%) ng×h/mL in those with moderate hepatic impairment, and 305 (24.8%) ng/mL and 2740 (44.0%) ng×h/mL in those with severe hepatic impairment.
Intracellular Pharmacokinetics
In non-dividing 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
The medicinal product is indicated in combination with other antiretroviral medicinal products for the treatment of HIV-1 infected patients.
The medicinal product is indicated for the treatment of HIV-1 infected adolescents aged 12 to < 18 years with resistance to nucleoside reverse transcriptase inhibitors (NRTIs) or toxicity precluding the use of first-line antiretroviral agents.
Selection of the medicinal product for the treatment of HIV-1 infected patients previously treated with antiretroviral agents should be based on individual viral resistance testing data and/or patient treatment history.
Hepatitis B
The medicinal product 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 "Pharmacodynamics" and "Adverse reactions");
- decompensated liver disease (see sections "Pharmacodynamics", "Special warnings and precautions for use" and "Adverse reactions").
The medicinal product is indicated for the treatment of chronic hepatitis B in adolescents aged 12 to < 18 years with:
- compensated liver disease, with evidence of active immune system disease, i.e. active viral replication, persistent elevation of serum ALT levels, and histological evidence of active inflammation and/or fibrosis (see sections "Pharmacodynamics", "Special warnings and precautions for use" and "Adverse reactions").
Contraindications.
Hypersensitivity to the active substance or to any of the excipients of the medicinal product.
Paediatric use 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 data and the known elimination pathway of tenofovir, the potential for CYP450-mediated interactions between tenofovir and other medicinal products is considered low.
Not recommended for concomitant use. The medicinal product should not be used with other medicinal products containing tenofovir disoproxil fumarate or tenofovir alafenamide.
The medicinal product should not be used concomitantly with adefovir dipivoxil.
Didanosine. Concomitant use of tenofovir disoproxil fumarate and didanosine is not recommended (see section "Special warnings and precautions for use" 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 concomitantly administered medicinal products.
Use of tenofovir disoproxil fumarate should be avoided with concomitant or recent use of nephrotoxic medicinal products. These include, for example, aminoglycosides, amphotericin B, foscarnet, ganciclovir, pentamidine, vancomycin, cidofovir, and interleukin-2 (see section "Special warnings and precautions for use").
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 (increase is denoted by "↑", decrease 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
| Medicinal product by therapeutic area (dose in milligrams) |
Effect on drug levels, mean percentage change AUC, Cmax, Cmin |
Recommendation for coadministration 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 precautions"). |
| 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 precautions"). |
| 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 precautions"). |
| Nucleoside reverse transcriptase inhibitors (NRTIs) |
||
| Didanosine |
Coadministration of tenofovir disoproxil fumarate and didanosine results in 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. Coadministration of tenofovir disoproxil fumarate and didanosine at a dose of 400 mg per day has been associated with significant reduction 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 frequency of virological treatment failure in several studied HIV-1 treatment regimens. |
Coadministration of tenofovir disoproxil fumarate and didanosine is not recommended (see section "Special precautions"). |
| Adefovir dipivoxil |
AUC: ↔ Cmax: ↔ |
Tenofovir disoproxil fumarate should not be coadministered with adefovir dipivoxil (see section "Special precautions"). |
| 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-33100722: 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 coadministration 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 booster (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 precautions"). |
| 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 coadministration 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 booster (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 precautions"). |
| 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 precautions"). |
| 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 precautions"). |
| 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 precautions"). |
| 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 coadministration 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 booster (e.g., ritonavir or cobicistat) has not been established. This combination should be used with frequent monitoring of renal function (see section "Special precautions"). |
| 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 coadministration 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 booster (e.g., ritonavir or cobicistat) has not been established. This combination should be used with frequent monitoring of renal function (see section "Special precautions"). |
| 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 coadministration 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 booster (e.g., ritonavir or cobicistat) has not been established. This combination should be used with frequent monitoring of renal function (see section "Special precautions"). |
| 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 precautions"). |
| 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 coadministration 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 booster (e.g., ritonavir or cobicistat) has not been established. This combination should be used with frequent monitoring of renal function (see section "Special precautions"). |
| 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 % |
Coadministration 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 precautions"). |
| 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 administration of ledipasvir/sofosbuvir. Sequential dosing (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 concurrently 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 therapy with tenofovir disoproxil fumarate, 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 it has not been demonstrated that effective viral suppression with antiretroviral medicinal products substantially reduces the risk of sexual transmission, residual risk cannot be excluded. Preventive measures to avoid transmission should be taken in accordance with national recommendations.
Chronic hepatitis B. Patients should be informed that there is no evidence that tenofovir disoproxil fumarate prevents the risk of transmission of HBV to others via sexual contact or blood exposure. Appropriate preventive measures should continue to be used.
Concomitant use with other medicinal products
- Do not use with other medicinal products containing tenofovir disoproxil fumarate or tenofovir alafenamide.
- Do not use concomitantly with adefovir dipivoxil.
- Concomitant use of tenofovir disoproxil fumarate and didanosine is not recommended, as it leads to 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 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 together with tenofovir disoproxil fumarate has been associated with reports of high rates of virological failure in several studied combinations for the treatment of HIV-1 infection.
Nucleoside/nucleotide triple therapy
Reports have emerged of high rates of early virological failure and resistance development in HIV patients when tenofovir disoproxil fumarate was combined with lamivudine and abacavir, as well as with lamivudine and didanosine administered once daily.
Effects on kidneys and bones in adults
Effects on renal function
Tenofovir is primarily eliminated by the kidneys. Reports 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
Estimation of creatinine clearance is recommended in all patients prior to initiating tenofovir disoproxil fumarate therapy. Renal function (creatinine clearance and serum phosphate levels) should be checked at 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 are < 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 reassessed within 1 week, including measurement of blood glucose, blood potassium, and urine glucose concentration (see section "Adverse reactions", proximal tubulopathy). Discontinuation of tenofovir disoproxil fumarate 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 treatment should also be considered in cases of progressive decline in renal function if no other cause is identified.
Concomitant use and risk of nephrotoxicity
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 following 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. When the medicinal product 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 via the same renal pathway, including human organic anion transporters (hOAT) 1 and 3 or MRP 4 (e.g., cidofovir – a known nephrotoxic medicinal product). These renal transport proteins may contribute to tubular secretion and partial 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. Unless clearly necessary, concomitant use of medicinal products eliminated via the same renal pathway is not recommended. 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 very limitedly studied in adult patients with renal impairment (CrCl < 80 mL/min).
Adult patients with CrCl < 50 mL/min, including patients on haemodialysis
Data on the safety of tenofovir disoproxil fumarate in patients with renal impairment are limited. Therefore, tenofovir disoproxil fumarate should be prescribed only when the expected benefit outweighs the potential risks. Tenofovir disoproxil fumarate is not recommended for patients with acute renal failure (CrCl < 30 mL/min) or those requiring haemodialysis. If no alternative treatment is available, the dosing interval should be adjusted and careful monitoring of renal function should be performed (see sections "Pharmacokinetics" and "Posology and method of administration").
Effects on bones
In HIV-infected patients during a 144-week controlled clinical trial comparing tenofovir disoproxil fumarate with stavudine in combination with lamivudine and efavirenz in antiretroviral-naïve patients, both treatment groups showed a slight decrease in bone mineral density (BMD) at the hip and spine. Over 144 weeks, the decrease in spine BMD and changes in bone biomarkers were significantly greater in the tenofovir disoproxil fumarate group. Decreases in hip BMD were significantly greater in this group up to week 96. However, after 144 weeks, no increased risk of fractures or clinically significant bone abnormalities was observed.
In other studies (prospective and cross-sectional), the most pronounced BMD reduction was observed in patients receiving tenofovir disoproxil fumarate as part of a regimen containing a boosted protease inhibitor. Alternative treatment regimens should be considered for patients with osteoporosis who are at high risk of fractures.
Bone abnormalities (rarely leading to fractures) may be associated with proximal renal tubulopathy (see section "Adverse reactions"). If bone abnormalities are suspected, appropriate consultations should be sought.
Effects on kidneys and bones in the paediatric population
There are uncertainties regarding the long-term effects of bone and renal 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 treatment (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 treatment as in adults (see above).
Treatment of renal disorders
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 assessed 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 detected renal abnormalities, consultation with a nephrologist is required to consider the possibility of interrupting tenofovir disoproxil fumarate treatment. Interruption of tenofovir disoproxil fumarate treatment should also be considered in cases of progressive decline in renal function if no other cause is identified.
Concomitant use and risk of nephrotoxicity
See recommendations for adults above.
Renal impairment
Tenofovir disoproxil fumarate is not recommended for 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.
Effects on bones
The medicinal product may cause a decrease in BMD. The impact of BMD changes associated with tenofovir disoproxil fumarate on long-term bone health and future fracture risk is currently unknown (see section "Pharmacodynamics").
If bone abnormalities are detected or suspected in children, consultation with an endocrinologist and/or nephrologist is required.
Liver disease
Data on safety and efficacy of the medicinal product in patients with liver transplantation are very limited.
Safety and efficacy data for tenofovir disoproxil fumarate in patients infected with hepatitis B and with decompensated liver disease and 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 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 treatment discontinuation. Acute hepatitis flares have also been reported in patients who discontinued hepatitis B treatment. Post-treatment flares are usually associated with increased 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 severe and sometimes fatal.
Hepatitis C or D co-infection. Data on the efficacy of tenofovir in patients with hepatitis C or D co-infection are lacking.
HIV-1 and hepatitis B co-infection. Due to the risk of HIV resistance development, tenofovir disoproxil fumarate should be used in HIV/HBV co-infected patients only as part of an appropriate antiretroviral combination regimen. Patients with previous liver function disorders, including chronic active hepatitis, have a higher frequency of liver function abnormalities during combination antiretroviral therapy (cART), and should be monitored according to standard practice. If there is evidence of worsening liver disease in such patients, consideration should be given to interrupting or discontinuing treatment. 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
Increased plasma concentrations of tenofovir are observed when tenofovir disoproxil fumarate is used concomitantly with ledipasvir/sofosbuvir, sofosbuvir/velpatasvir, or sofosbuvir/velpatasvir/voxilaprevir, particularly when combined 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 considered, especially 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 occur in patients. Such changes may be partly related to both therapy and lifestyle. Regarding lipids, there is evidence of treatment impact in some cases, 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.
Postnatal mitochondrial dysfunction following in utero exposure
Nucleoside and nucleotide analogues cause varying degrees of mitochondrial injury, particularly with stavudine, didanosine, and zidovudine. Reports of mitochondrial dysfunction in HIV-negative infants exposed to nucleoside analogues in utero and/or postnatally have been reported. This primarily concerns treatment regimens containing zidovudine. The main adverse reactions reported were haematological disorders (anaemia, neutropenia) and metabolic disorders (hyperlactataemia, hyperlipasaemia). These events were often transient. Rare reports of later-onset neurological disorders (hypertension, 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/nucleotide analogues associated with serious clinical disorders of unknown aetiology, particularly neurological disorders. These findings do not affect current national recommendations for antiretroviral treatment 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 cART, an inflammatory reaction to asymptomatic or residual opportunistic pathogens may occur, which may cause serious clinical conditions or worsening of symptoms. Such reactions are typically observed within the first few weeks or months after 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 to develop during immune reconstitution; however, the time to onset of disease has been highly variable, 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 cART exposure. Patients should seek medical advice if they experience joint pain, joint stiffness, or difficulty moving.
Elderly patients
The use of tenofovir disoproxil has not been studied in patients aged 65 years and older. Elderly patients often have reduced renal function; therefore, caution should be exercised when prescribing tenofovir disoproxil fumarate to these patients.
The medicinal product contains lactose monohydrate; therefore, patients with rare hereditary problems of galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption should not take this medicinal product.
Use during pregnancy or breastfeeding.
Pregnancy
A large amount of data from use in pregnant women (over 1000 completed pregnancies) indicates no teratogenic or embryotoxic/fetotoxic effects associated with tenofovir disoproxil fumarate. Animal studies have not shown any toxic effects on reproductive function. Tenofovir disoproxil fumarate may be used during pregnancy if necessary.
Breastfeeding
Tenofovir has been detected in human breast milk. There is insufficient information on the effects of tenofovir on newborns/infants. Therefore, the medicinal product should not be used during breastfeeding.
Generally, HIV- and HBV-infected women are not recommended 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 not shown any adverse effects of tenofovir disoproxil fumarate on fertility.
Ability to drive and use machines.
No studies on the effect on the ability to drive vehicles or operate machinery have been conducted. Patients should be informed that dizziness may occur during treatment with tenofovir disoproxil fumarate.
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:
- For patients who are positive for hepatitis B virus antigen (HBeAg) without cirrhosis, treatment should continue for at least 6–12 months after confirmed HBe seroconversion (loss of hepatitis B virus antigens and DNA with detection of anti-HBe) or until HBs seroconversion or treatment failure occurs (see section "Special Warnings and Precautions for Use"). After discontinuation of treatment, ALT levels and hepatitis B virus DNA in serum should be monitored regularly to detect any late virological relapses;
- For patients who are negative for hepatitis B virus antigen without cirrhosis, treatment should continue at least until HBs seroconversion or until signs of treatment failure appear. In cases of prolonged treatment lasting longer than 2 years, periodic re-evaluation of therapy is recommended to confirm that the chosen treatment remains effective for the patient.
Children
HIV-1. For adolescents aged 12 to < 18 years weighing ≥ 35 kg, the recommended dose is 1 tablet once daily, taken orally with food (see sections "Pharmacodynamics" and "Adverse Reactions").
Chronic Hepatitis B. For adolescents aged 12 to < 18 years weighing ≥ 35 kg, the recommended dose is 1 tablet once daily, taken orally with food (see sections "Pharmacodynamics" and "Adverse Reactions"). The optimal duration of treatment is currently unknown.
Missed Dose
If a patient misses a dose and less than 12 hours have passed since the scheduled time, the patient should take the missed dose with food as soon as possible, then continue with the regular dosing schedule. If a patient misses a dose and more than 12 hours have passed since the scheduled time (i.e., the next dose is nearly due), the patient should not take the missed dose but continue treatment according to the regular schedule.
If vomiting occurs within 1 hour after taking the medication, the patient should take another tablet. If vomiting occurs more than 1 hour after taking the medication, there is no need to take another tablet.
Special Patient Groups
Elderly Patients. Currently, there are no data available to provide 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 at increased risk of tenofovir exposure.
Adults. Data on the safety and efficacy of tenofovir disoproxil fumarate in patients with moderate and severe renal impairment (CrCl < 50 mL/min) are limited. Long-term safety data in patients with mild renal impairment (CrCl 50–80 mL/min) are lacking. Therefore, tenofovir disoproxil fumarate should be used in patients with renal impairment only if the potential benefit outweighs the risk. Dose interval adjustment is recommended for patients with CrCl < 50 mL/min, including those undergoing hemodialysis.
Mild Renal Impairment (CrCl 50–80 mL/min). Limited clinical trial data in patients with mild renal impairment support once-daily administration of tenofovir disoproxil fumarate.
Moderate Renal Impairment (CrCl 30–49 mL/min). Administration of 1 tablet every 48 hours may be considered based on pharmacokinetic modeling of single-dose data in HIV-negative and hepatitis B virus-negative 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 in these patients should be closely monitored (see sections "Pharmacokinetics" and "Special Warnings and Precautions for Use").
Severe Renal Impairment (CrCl < 30 mL/min) and Patients on Hemodialysis. Appropriate dose adjustment cannot be applied due to the lack of tablets with alternative active ingredient content; therefore, use of the medicinal product in these patient groups is not recommended. If no alternative therapy is available, extended dosing intervals may be considered as follows:
- In severe renal impairment: 1 tablet every 72–96 hours (2 times per week);
- In patients on hemodialysis: 1 tablet every 7 days after completion of a hemodialysis session*.
* Generally, once weekly dosing is assumed, based on 3 hemodialysis sessions per week, each lasting approximately 4 hours, or after 12 hours of cumulative hemodialysis.
These dose interval adjustments have not been confirmed in clinical trials. Modeling suggests that prolonged dosing intervals with film-coated tablets may not be optimal and could lead to increased toxicity and possibly suboptimal response. Therefore, clinical response and renal function should be monitored (see sections "Pharmacokinetics" and "Special Warnings and Precautions for Use").
No dosage recommendations can be provided for patients not on hemodialysis with CrCl < 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 "Pharmacokinetics" and "Special Warnings and Precautions for Use").
When discontinuing the medicinal product in patients with chronic hepatitis B, with or without concomitant HIV infection, patients should be closely monitored for signs of hepatitis flare (see section "Special Warnings and Precautions for Use").
Administration
Tablets should be taken once daily, orally, with food.
If patients have difficulty swallowing, the tablets may be crushed and dissolved in 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 and weighing < 35 kg have not been established. No data are available.
Overdose.
Symptoms
In the event of overdose, patients should be observed 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 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. Renal impairment, renal failure, and rare cases of proximal renal tubulopathy (including Fanconi syndrome) have been reported rarely in patients receiving tenofovir disoproxil fumarate, sometimes leading to bone abnormalities (rarely fractures). Monitoring of renal function is recommended for patients taking the medicinal product (see section "Dosage and administration").
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 gastrointestinal events of mild to moderate severity. Approximately 1% of patients receiving tenofovir disoproxil fumarate discontinued treatment due to gastrointestinal events.
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 common 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.
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, comparative, controlled 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.
Clinical trials in hepatitis B. Assessment of adverse reactions in hepatitis B clinical trials is primarily based on results from two double-blind, comparative, controlled trials in which 641 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. 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 reported in patients treated with tenofovir disoproxil fumarate was 1.41 mL/min/year (by Cockcroft-Gault equation) and 0.74 mL/min/1.73 m²/year (by MDRD equation).
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 and tenofovir disoproxil fumarate (n = 45), or entecavir (n = 22) for 48 weeks.
In the tenofovir disoproxil fumarate treatment group, 7% of patients discontinued treatment due to adverse reactions, and 9% of patients had confirmed serum creatinine increase ≥ 0.5 mg/dL or confirmed serum phosphate level < 2 mg/dL by week 48. There was no statistically significant difference between the tenofovir combination group and the entecavir group. At week 168, discontinuation due to intolerance was observed in 16% (7 of 45) of patients in the tenofovir disoproxil fumarate group, 4% (2 of 45) in the emtricitabine and tenofovir disoproxil fumarate group, and 14% (3 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 of 45) of patients in the tenofovir disoproxil fumarate group, 13% (6 of 45) in the emtricitabine and tenofovir disoproxil fumarate group, and 9% (2 of 22) in the entecavir group.
At week 168 in this population of patients with decompensated liver disease, the mortality rate was 13% (6 of 45) in the tenofovir disoproxil fumarate group, 11% (5 of 45) in the emtricitabine and tenofovir disoproxil fumarate group, and 14% (3 of 22) in the entecavir group. The incidence of hepatocellular carcinoma was 18% (8 of 45) in the tenofovir disoproxil fumarate group, 7% (3 of 45) in the emtricitabine and tenofovir disoproxil fumarate group, and 9% (2 of 22) in the entecavir group.
It has been reported that patients with a high baseline score according to the Child-Pugh-Turcotte classification have an increased 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 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 presented in order of decreasing severity. Adverse reactions by frequency are defined as very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 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
| Organ system classes and frequency |
Adverse reactions |
| Nutrition and metabolism 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, abdominal distension, 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 |
|
| Uncommon |
Rhabdomyolysis1, muscle weakness1 |
| Rare |
Osteomalacia (manifesting as bone pain and infrequently contributing to 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 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 condition.
2 The adverse reaction was identified during post-marketing surveillance but was not observed during randomized controlled trials or the expanded access program for 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).
Description of selected adverse reactions
HIV-1 and Hepatitis B
Renal failure. Since the drug may lead to renal impairment, monitoring of renal function is recommended (see sections "Special precautions" 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 precautions").
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, increasing the risk of didanosine-related adverse reactions (see section "Interaction with other medicinal products and other forms of interaction"). Cases of pancreatitis and lactic acidosis, sometimes fatal, have been rarely reported.
Metabolic disturbances. Body weight and levels of lipids and blood glucose may increase during antiretroviral therapy (see section "Special precautions").
Immune Reconstitution Syndrome. In HIV-infected patients with severe immune deficiency at the time of initiation of 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 time to onset has been highly variable, and these events may occur many months after initiation of treatment (see section "Special precautions").
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 this event is unknown (see section "Special precautions").
Hepatitis B
Hepatitis flare during treatment. In clinical trials involving treatment-naïve patients, ALT elevations during treatment exceeding 10 times the upper limit of normal and doubling the baseline level were observed in 2.6% of patients receiving tenofovir disoproxil fumarate. The median time to ALT elevation was 8 weeks and was managed with continued treatment. In most cases, these ALT elevations were associated with a ≥ 2 log10 copies/mL reduction in viral load that preceded or coincided with the ALT increase. Monitoring of liver function is recommended during treatment (see section "Special precautions").
Hepatitis flare after discontinuation of treatment. After stopping hepatitis B therapy in patients infected with hepatitis B virus, clinical and laboratory signs of hepatitis flare have occurred (see section "Special precautions").
Use in adolescents
HIV-1
Adverse reactions were evaluated in one randomized trial (Study GS-US-104-0321) involving 87 HIV-1-infected adolescent 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 adolescent patients receiving tenofovir disoproxil fumarate were consistent with those observed in adults during clinical trials of tenofovir disoproxil fumarate (see sections "Pharmacodynamics" and "Summary table of adverse reactions").
In HIV-1-infected adolescents, Z-scores of BMD observed during tenofovir disoproxil fumarate treatment were lower than those observed with placebo.
Chronic Hepatitis B
Adverse reactions were evaluated in one randomized trial (Study GS-US-174-0115) involving 106 adolescent 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. Adverse reactions observed in adolescent patients receiving tenofovir disoproxil fumarate 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 were observed in HBV-infected adolescents. The Z-score of BMD observed in patients receiving tenofovir disoproxil fumarate was comparable to that in patients receiving placebo (see sections "Pharmacodynamics" and "Special precautions").
Other special patient groups
Elderly patients. Clinical studies of tenofovir disoproxil fumarate in patients aged 65 years and older 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 precautions").
Patients with renal impairment. Since tenofovir disoproxil fumarate may lead to nephrotoxicity, renal function should be monitored in patients with renal impairment who are taking the drug (see sections "Pharmacokinetics", "Special precautions", and "Dosage and administration"). Tenofovir disoproxil fumarate is not recommended for use in children with impaired renal function (see sections "Special precautions" and "Dosage and administration").
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. Keep out of the reach of children.
Packaging. 30 film-coated tablets in a bottle with a silica gel desiccant. 1 bottle per cardboard box.
Prescription status. Prescription only.
Manufacturer.
Strides Pharma Sciences Limited.
Manufacturer's address and location of operations.
No. 36/7, Suragadajakkana Halli, Indlavadi Cross, Anekal Taluk, Bangalore, Karnataka 562106, India.