ATX: J.05.A.F.07 Tenofovir
Mechanism of Action
Tenofovir disoproxil fumarate is the fumarate salt of the prodrug tenofovir disoproxil. Tenofovir disoproxil is absorbed and converted to the active ingredient tenofovir, which is an analog of nucleoside monophosphate (nucleotide). Tenofovir is then converted to the active metabolite, tenofovir diphosphate, which is an obligate chain terminator, by constructively expressed cellular enzymes.
Tenofovir diphosphate has an intracellular half-life of 10 hours in activated peripheral blood mononuclear cells and 50 hours at rest.
Tenofovir diphosphate inhibits HIV-1 reverse transcriptase and hepatitis B virus (HBV) polymerase through competition by direct binding to the active site of the enzyme with the natural deoxyribonucleotide substrate and DNA chain breakage after incorporation into it.
Tenofovir diphosphate is a weak inhibitor of cellular polymerases α, β and γ.
In in vitro assays, tenofovir at concentrations up to 300 μmol/L also showed no effect on mitochondrial DNA synthesis or on lactic acid production.
Activity against HIV
Activity against HIV in vitro
The concentration of tenofovir required for 50% inhibition (EC50 – 50% effective concentration) 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 peripheral blood mononuclear cells.
Tenofovir is also active against HIV-1 subtypes A, C, D, E, F, G and O, as well as against HIVBal in primary monocytes/macrophages.
Tenofovir also shows in vitro activity against HIV-2 with a 50% effective EC50 concentration of 4.9 μmol/L in MT-4 cells.
Activity against HBV
In vitro activity against HBV
The in vitro antiviral activity of tenofovir against HBV was evaluated on the HepG2 2 cell line.2.15. EU50 values for tenofovir ranged from 0.14 to 1.5 μmol/L, and CC50 values (50% cytotoxic concentration) exceeded 100 μmol/L.
Resistance
HIV-1 strains with reduced sensitivity to tenofovir and a K65R substitution in the reverse transcriptase gene have been isolated in vitro and in some patients. Tenofovir disoproxil fumarate should be avoided in patients who have previously received antiretroviral therapy whose strains contain the K65R mutation.
In clinical trials in patients previously receiving antiretroviral therapy, the anti-HIV activity of 300 mg tenofovir disoproxil fumarate against nucleoside inhibitor-resistant strains of HIV-1 was evaluated. The results showed that patients whose HIV expressed 3 or more mutations associated with thymidine analogues, including M41L or L210W substitutions in reverse transcriptase, showed a reduced response to therapy with 300 mg tenofovir disoproxil fumarate.
HBV resistance
HBV polymerase mutations associated with resistance to tenofovir disoproxil fumarate have not been identified. In cellular models, variants of HBV expressing substitutions rtV173L, rtL180M, and rtM2041/V associated with resistance to lamivudine and telbivudine demonstrated sensitivity to tenofovir 0.7-3.4 times that of the “wild-type” virus.
The HBV strains expressing substitutions rtL180M, rtT184G, rtS202G/I, rtM204V, and rtM250V associated with entecavir resistance showed 0.6-6.9 times greater sensitivity to tenofovir than wild-type virus.
The HBV strains expressing rtA181V and rtN236T substitutions associated with adefovir resistance showed 2.9-10 times greater sensitivity to tenofovir than wild-type virus.
Viruses containing the rtA 181T substitution remained sensitive to tenofovir, with EU50 values 1.5-fold greater than those of the “wild-type” virus.
Pharmacokinetics:
Tenofovir disoproxyl fumarate is a water-soluble ester of the prodrug that is rapidly converted in vivo to tenofovir and formaldehyde. Tenofovir is converted intracellularly to tenofovir monophosphate and the active ingredient tenofovir diphosphate.
Absorption
After oral administration in HIV-infected patients tenofovir disoproxil fumarate is rapidly absorbed and converted to tenofovir.
The ingestion of multiple doses of tenofovir disoproxil fumarate with food by HIV-infected patients resulted in mean (coefficient of variation, % [CV, %]) values for tenofovir Cmax, AUC and Cmin of 326 (36.6%) ng/mL, 3324 (41.2%) ng*h/mL and 64.4 (39.4%) ng/mL, respectively.
The maximum concentrations of tenofovir are observed in serum within 1 hour after fasting and within 2 hours when taken with food. When tenofovir disoproxil fumarate was administered to patients on an empty stomach, the bioavailability was approximately 25%. Administration of tenofovir disoproxil fumarate with a fat-rich meal increased bioavailability, with the AUC of tenofovir increasing by approximately 40% and the Cmax by approximately 14%. After the first dose of tenofovir disoproxil fumarate following a fat-rich meal, median serum Cmax values ranged from 213 to 375 ng/mL. However, ingestion of tenofovir disoproxil fumarate with a low-fat meal has no significant effect on tenofovir pharmacokinetics.
Distribution
After intravenous administration, the equilibrium distribution concentration of tenofovir was estimated to be approximately 800 ml/kg. After oral administration of tenofovir disoproxil fumarate, tenofovir is distributed to many tissues, with the highest concentrations observed in the kidneys, liver and intestinal epithelium at different sites (preclinical studies).
In vitro binding of tenofovir to plasma or serum proteins was less than 0.7 and 7.2%, respectively, in the concentration range of tenofovir from 0.01 to 25 µg/ml.
Metabolism
In vitro studies have shown that neither tenofovir disoproxil fumarate nor tenofovir are substrates of CYP450 enzymes. Moreover, at concentrations significantly higher (approximately 300-fold) than those observed in vivo, tenofovir did not inhibit in vitro drug metabolism mediated by any of the major human CYP450 isoforms involved in biotransformation (CYP3A4, CYP2D6, CYP2C9, CYP2E1 or CYP1A1/2).
Tenofovir disoproxil fumarate at a concentration of 100 μmol/L had no effect on any of the CYP450 isoforms except CYP1A1/2, where there was a small (6%) but statistically significant decrease in CYP1A1/2 substrate metabolism. Based on this information, it can be concluded that there is little likelihood of clinically significant interactions between tenofovir disoproxil fumarate and drugs whose metabolism is mediated by CYP450.
Tenofovir is excreted primarily by the kidneys, both by filtration and by the active tubular transport system, with approximately 70-80% of the dose being excreted unchanged in the urine following 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 (approximately 210 ml/min), which exceeds the glomerular filtration rate. This indicates that tubular secretion is an important part of tenofovir excretion.
After oral administration, the final half-life of tenofovir is 12 to 18 hours.
The active tubular transport system of secretion has been found to include uptake of tenofovir by proximal tubule cells via human organic anion transporters (hOAT) 1 and 3, and its excretion into the urine via multidrug resistance marker protein 4 (MRP 4).
Linearity-nonlinearity
The pharmacokinetics of tenofovir were independent of the dose of tenofovir disoproxil fumarate between 75 and 600 mg and did not change with repeated administration at any dose level.
Pharmacokinetics in Special Patient Groups
Elderly Patients
The pharmacokinetics of tenofovir in elderly patients (>65 years) have not been studied.
Gender
Limited data on the pharmacokinetics of tenofovir in women indicate no significant sex-specific effects.
Race
There have been no specific studies of pharmacokinetics in different ethnic groups.
Children
HIV-1
The equilibrium pharmacokinetic parameters of tenofovir were assessed in 8 children (ages 12 to 18 years) with a body weight of > 35 kg infected with HIV-1. Mean (± SD) Cmax and AUCtau values were 0.38 ± 0.13 µg/ml and 3.39 ± 1.22 µg*h/ml, respectively.
The exposure of tenofovir achieved in adolescents receiving daily oral doses of 300 mg of tenofovir disoproxil fumarate was similar to that achieved in adults receiving single daily doses of 300 mg of tenofovir disoproxil fumarate.
Chronic hepatitis B
. Equilibrium exposure to tenofovir in children (ages 12 to 18 years) infected with hepatitis B virus who received an oral daily dose of 300 mg of tenofovir disoproxil fumarate was similar to exposures achieved in adults who received once-daily doses of 300 mg of tenofovir disoproxil fumarate.
In children younger than 12 years of age or in children with impaired renal function, studies of the pharmacokinetics of 300 mg tenofovir disoproxil fumarate have not been performed.
Renal dysfunction
Parameters of tenofovir pharmacokinetics were determined after administration of a single dose of 300 mg of tenofovir disoproxil fumarate in 40 adult patients without HIV or HBV infection with varying degrees of renal impairment, determined according to baseline creatinine clearance (CK) values (renal function is not impaired if CK > 80 mL/min, mild impairment if the CK is 50-79 mL/min, moderate impairment if the CK is 30-49 mL/min, and severe impairment if the CK is 10-29 mL/min).
Compared with patients with normal renal function, mean (%CV) tenofovir exposure increased from 2,185 (12%) ng*h/mL in those with CK > 80 mL/min to, respectively, 3,064 (30%) ngh/mL, 6,009 (42%) ng*h/mL, and 15,985 (45%) ng*h/mL in patients with mild, moderate, and severe renal impairment.
Lengthening the interval between drug administration is expected to result in higher peak plasma concentrations and lower Cmin levels in patients with impaired renal function compared to patients with normal renal function. The clinical significance of this is unknown.
In patients with end-stage renal failure (CK < 10 mL/min) who required hemodialysis, tenofovir concentrations increased significantly between dialysis within 48 hours, reaching a mean Cmax of 1032 ng/mL and a mean AUC0-48 of 42857 ng*h/mL.
It is recommended that the interval between doses of 300 mg of tenofovir disoproxil fumarate be modified in adult patients with CK < 50 ml/min or in patients who already have end-stage renal failure and require dialysis.
The pharmacokinetics of tenofovir in patients without hemodialysis with a KC < 10 ml/min and in patients with terminal renal failure whose status is controlled by peritoneal or other forms of dialysis have not been studied. Pharmacokinetic studies of tenofovir in children with renal insufficiency have not been conducted. No data on dosing recommendations are available.
Hepatic impairment
A single dose of 300 mg of tenofovir disoproxil fumarate has been taken in patients without HIV or HBV infection with varying degrees of hepatic impairment as defined by the Child-Pugh classification.
No significant changes in tenofovir pharmacokinetic parameters were observed in patients with hepatic impairment, suggesting no need for dose adjustment. The mean (% CV) Cmax and AUC0-∞ values of tenofovir were 223 (34.8%) ng/mL and 2050 (50.8%) ng*h/mL, respectively, in those without hepatic impairment, 289 (460%) ng/mL and 2310 (43.5%) ng*h/mL in subjects with moderate hepatic impairment 305 (24.8%) ng/mL, and 2740 (44.0%) ng*h/mL in subjects with severe hepatic impairment.
Intracellular pharmacokinetics
The half-life of tenofovir diphosphate was found to be approximately 50 hours in human peripheral blood mononuclear cells (PBMCs), whereas in PBMCs stimulated with phytohemagglutinin it was approximately 10 hours.
Indications
HIV-1 infection
The treatment of HIV-1 infection in adults in combination with other antiretroviral drugs.
The treatment of HIV-1 infection in children aged 12 to 18 years with resistance to nucleoside reverse transcriptase inhibitors, or toxicity that precludes the use of first-line antiretroviral drugs.
Hepatitis B
The treatment of chronic hepatitis B in adults with:
- compensated liver disease with evidence of active viral replication, persistent elevated serum alanine aminotransferase (ALT) activity and histologically confirmed active inflammatory process and/or fibrosis;
- proven HBV resistance to lamivudine;
- decompensated liver disease.
The treatment of chronic hepatitis B in children aged 12 to 18 years with
.
Active ingredient
Tenofovir
Composition
Active ingredient:
Tenofovir disoproxil fumarate 300 mg
Excipients:
Each film-coated tablet contains:
Core: sodium carboxymethyl starch (primogel) – 33.0 mg, sodium stearyl fumarate – 11.8 mg, sodium croscarmellose – 42.0 mg, lactose monohydrate – 72.0 mg, hypromellose E-15 – 9.6 mg, microcrystalline cellulose – 131.6 mg.
Prepared water-soluble film coating – 18.0 mg.
(Shell composition: hypromellose – 74.2%, macrogol 6000-14.3%, titanium dioxide – 3.5%, talc – 2.3%, iron oxide red dye – 1.4%, iron oxide yellow dye – 4.3%).
How to take, the dosage
To be taken by mouth with food. The tablet should be swallowed whole with water. Tablets should not be chewed or crushed.
The treatment should be started and monitored by a doctor with experience in treating HIV infection and/or chronic hepatitis B.
The choice of tenofovir to treat HIV-1-infected patients who have previously been treated should be based on verification of individual viral resistance and/or the patient’s treatment history.
Adults
The recommended dose of the drug for treatment of HIV and chronic hepatitis B is 300 mg once daily orally, with food.
Chronic hepatitis B
The optimal duration of treatment is unknown. Discontinuation of treatment may be considered as follows:
– Treatment of HBeAg-positive patients without cirrhosis should continue for at least 6-12 months after confirmation of HBe seroconversion (disappearance of HBeAg and HBV DNA with the appearance of anti-HBs) or until HBs seroconversion or loss of efficacy. After discontinuation of treatment, serum ALT and hepatitis B virus DNA levels should be checked regularly to detect possible late relapses of viraemia.
– Treatment of patients with HBeAg-negative hepatitis B without cirrhosis should continue at least until HBs seroconversion or signs of treatment failure appear. In the case of prolonged treatment lasting more than 2 years, a regular reevaluation of treatment is recommended to confirm the patient’s acceptability to continue the chosen therapy.
Children 12 to 18 years of age
HIV-1: At 12 to 18 years of age and with a body weight ≥ 35 kg, the recommended dose of the drug is 300 mg once daily orally, with food. The tablet should be swallowed whole with water. The tablets should not be chewed or crushed.
In exceptional cases, a tablet of the drug Virfoten can be taken immediately after dissolving in about 100 ml of water, orange juice or grape juice.
Chronic hepatitis B: At 12 to 18 years of age and with a body weight ≥ 35 kg, the recommended dose is 300 mg once daily orally, with food. The optimal duration of treatment has not yet been established.
The safety and efficacy of tenofovir in children with chronic hepatitis B between 2 and 12 years of age and with a body weight of < 35 kg have not been established.
Missed dose
- If a dose is missed and less than 12 hours have passed from the normal dosing time, the patient should take the drug with the meal as soon as possible and return to the normal dosing schedule.
- If more than 12 hours have passed since the missed dose and the next dose is approaching, the patient should not take the missed dose but take the next dose as per the usual dosing schedule.
If the patient vomits within 1 hour of taking the drug, another dose should be taken. If the patient vomits more than 1 hour after taking the drug, do not take another dose.
Special patient groups
Patients in the elderly
There are currently no data on which to base dosing recommendations for patients over 65 years of age.
Kidney disorders
Tenofovir is excreted with urine, so patients with impaired renal function have a longer elimination time of tenofovir.
Adults
The data on safety and efficacy of tenofovir in adult patients with moderate to severe renal impairment (KC<50 ml/min) are limited. Long-term safety in patients with mild renal impairment (CK50-80 ml/min) has not been evaluated. For this reason, in patients with impaired renal function tenofovir should be used when the potential benefit of treatment exceeds the potential risk of harm. Correction of the dosing interval is recommended for patients with a CKR < 50 ml/min.
Mild renal impairment (CKR 50-80 ml/min). The limited data from clinical studies suggest that a once-daily dosing regimen of tenofovir should be maintained for patients with mild renal impairment.
Moderate renal dysfunction (CKD 30-49 mL/min). A dose of 300 mg every 48 hours is recommended based on simulated single-dose pharmacokinetic data in volunteers without HIV or HBV infection with varying degrees of renal impairment, including those with end-stage renal failure requiring hemodialysis. However, such dosing has not been validated in clinical trials. Therefore, the clinical response to treatment and renal function in such patients should be closely monitored.
Severe renal function impairment (CK < 30 ml/min) and patients on hemodialysis. Due to the inability to make dosing adjustments, the use of the drug is contraindicated in patients in this group.
In children
Tenofovir is not recommended for use in children with impaired renal function.
Hepatic impairment
There is no need for dose adjustment in patients with hepatic impairment. Patients with chronic hepatitis B (with or without concomitant HIV infection) should be closely monitored if they have discontinued tenofovir, because there is a risk of hepatitis exacerbation after discontinuation of the drug.
Interaction
Interaction studies have only been performed in adults.
Based on the results of in vitro experiments and the known excretion pathway of tenofovir, the possibility of CYP450-mediated interactions involving tenofovir and other drugs is low.
Simultaneous use is not recommended
Tenofovir is contraindicated with other medicinal products containing tenofovir.
Tenofovir is contraindicated for use concomitantly with adefovir.
Didanosine
The concomitant use of tenofovir and didanosine is not recommended (see Special Precautions and Table 2).
Drugs that are excreted by the kidneys
Because tenofovir is primarily excreted by the kidneys, concomitant use of tenofovir with drugs that reduce renal function or compete for active tubular secretion by hOAT 1, hOAT 3 or MRP 4 transport proteins (such as cidofovir) may increase the serum concentration of tenofovir and/or drugs taken concomitantly.
The use of tenofovir with concomitant or recent use of nephrotoxic drugs (e.g., aminoglycosides, amphotericin B, foscarnet, ganciclovir, pentamidine, vancomycin, cidofovir and interleukin-2) should be avoided (see section “Special Indications”).
In view of the fact that tacrolimus may affect renal function, close monitoring is recommended when it is used concomitantly with tenofovir.
Other interactions
The interactions between tenofovir, protease inhibitors, and antiretroviral agents other than protease inhibitors are shown in Table 2 below (increases are indicated with “↑”, decreases with “↓”, no change with “↔”, twice daily with “b.i.d.” and once daily with “q.d.”).
Table 2. Interactions between tenofovir and other drugs
Medication by therapeutic route (dose in mg) | Impact on drug levels, mean percentage change in AUC, Cmax, Cmin | Recommendation for concomitant use with tenofovir disoproxil fumarate 300 mg | |
TOPPROFIXING | |||
Antiretroviral | |||
Protease inhibitors | |||
Atazanavir/Ritonavir (300 mg qd./100 mg q.d./300 mg q.d.) | Atazanavir: AUC: ↓ 25% Cmax: ↓ 28% Cmin : ↓ 26% Tenofovir: AUC: ↑ 37% Cmax: ↑ 34% Cmin: ↑ 29% | Dose adjustment is not necessary. Longer exposure to tenofovir may increase tenofovir-related adverse events, including renal pathology. Renal function should be monitored carefully. | |
Lopinavir/Ritonavir (400 mg b.i.d./ 100 mg b.i.d./300 mg q.d.) | Lopinavir/Ritonavir: No significant effect on lopinavir/ritonavir FC parameters. Tenofovir: AUC: ↑ 32% Cmax: ↔ Cmin: ↑ 51% | Dose adjustment is not required. Longer exposure to tenofovir may increase tenofovir-related adverse events, including renal pathology. Renal function should be monitored carefully. | |
Darunavir/Ritonavir (300 mg/100 mg b.i.d./ 300 mg q.d.) | Darunavir: There is no significant effect on the FC parameters of darunavir/ritonavir. Tenofovir: AUC: ↑ 22% Cmin: ↑ 37% | Dose adjustment is not required. Longer exposure to tenofovir may increase tenofovir-related adverse events, including renal pathology. Renal function should be monitored carefully. | |
Nucleoside reverse transcriptase inhibitors/p> | |||
Didanosine | Concomitant use of tenofovir and didanosine results in a 40-60% increase in systemic exposure to didanosine, which may increase the risk of didanosine-related adverse events. Infrequent, sometimes fatal, cases of pancreatitis and lactoacidosis have been reported. The concomitant administration of tenofovir and didanosine at a dose of 400 mg daily has been associated with a significant decrease in CD4 cell count, possibly due to intercellular interaction, which increases phosphorylated (i.e., active) didanosine. Reducing the dosage of didanosine to 250 mg administered with tenofovir has been associated with reports of a high rate of virologic treatment failure in several combinations studied to treat HIV-1 infection. | The concomitant use of tenofovir and didanosine is not recommended. | |
Adefovir | AUC: ↔, Cmax: ↔ | Tenofovir is contraindicated concomitantly with adefovir. | |
Entecavir | AUC: ↔, Cmax: ↔ | There were no clinically significant pharmacokinetic interactions when tenofovir was used concomitantly with encecavir. |
Studies performed with other drugs
No clinically significant pharmacokinetic interactions have been observed with the concomitant use of tenofovir with emtricitabine, lamivudine, indinavir, efavirenz, nelfinavir, saquinavir (enhanced ritonavir), methadone, ribavirin, rifampicin, tacrolimus and the hormonal contraceptive norgestimate/ethylestradiol.
Tenofovir should be taken simultaneously with food, because food increases the bioavailability of tenofovir.
Special Instructions
General
All patients infected with hepatitis B virus should be offered an HIV antibody test before starting tenofovir therapy.
HIV-1
While stable antiretroviral therapy, resulting in sustained suppression of the virus, significantly reduces the risk of sexual transmission, the risk cannot be completely eliminated. Precautions to prevent transmission should be taken according to national guidelines.
Chronic hepatitis B
Patients should be advised that tenofovir’s ability to prevent the risk of sexual or bloodborne transmission of HBV to others has not been proven. Appropriate precautions should be followed.
Simultaneous use with other medicinal products
The drug is contraindicated with other medicinal products containing tenofovir.
Tenofovir is contraindicated for concomitant use with adefovir.
The concomitant use of tenofovir and didanosine is not recommended. Concomitant use of tenofovir and didanosine leads to a 40-60% increase in systemic exposure to didanosine, which may increase the risk of didanosine-related adverse events (see section “Interaction with other medicinal products”). Rarely, pancreatitis and lactoacidosis have been reported, sometimes with fatal outcome. Concomitant use of tenofovir and didanosine at a dose of 400 mg per day was associated with a significant decrease in CD4 cell count, possibly due to intercellular interaction, which increases phosphorylated (that is, active) didanosine. The use of didanosine at a reduced dosage of 250 mg along with tenofovir therapy has been associated with reports of a high rate of virologic failure in several combinations studied for the treatment of HIV-1 infection.
Nucleoside/nucleotide triple therapy
There have been reports of high rates of virologic failure and early resistance in patients with HIV infection when tenofovir is combined with lamivudine and abacavir and with lamivudine and didanosine on a once-daily schedule.
Impact on renal function and bone function in adults
Impact on renal function
Tenofovir is primarily excreted by the kidneys. Renal failure, impaired renal function, elevated creatinine, hypophosphatemia, and proximal tubulopathy (including Fanconi syndrome) have been reported with tenofovir in clinical practice.
Renal function monitoring
We recommend CK determinations in all patients before treatment with tenofovir and monitoring of renal function (CK and serum phosphate levels) after 2-4 weeks of treatment, after 3 months of treatment, and every 3-6 months thereafter in patients without risk factors for renal function impairment.
For patients at increased risk of renal impairment, more frequent monitoring of renal function should be considered.
Management of patients with impaired renal function
If serum phosphate levels <1.5 mg/dL (0.48 mmol/L) or CK is reduced to < 50 mL/min in a patient receiving tenofovir, reassessment of renal function should be performed within 1 week, including determination of blood glucose, blood potassium, and urinary glucose concentrations.
Consideration should also be given to withdrawing treatment with tenofovir in patients with decreased CK to <50 mL/min or decreased serum phosphate levels to <1.0 mg/dL (0.32 mmol/L).
Cancellation of tenofovir treatment should also be considered in cases of progressive decline in renal function if no other cause has been determined.
Co-use with other drugs and risk of nephrotoxicity
The use of tenofovir with concurrent or recent use of nephrotoxic drugs (e.g., aminoglycosides, amphotericin B, foscarnet, ganciclovir, pentamidine, vancomycin, cidofovir and interleukin-2) should be avoided. If concomitant use of tenofovir and nephrotoxic agents cannot be avoided, renal function should be monitored weekly. In patients with risk factors for renal function impairment, coadministration of tenofovir with an enhanced protease inhibitor should be carefully evaluated.
The clinical evaluation of tenofovir has not been performed in patients taking drugs that are also excreted by the kidneys through human organic anion transporter proteins (hOAT) 1 and 3 or MRP4 (e.g., cidofovir, a known nephrotoxic drug). These renal transport proteins may be responsible for the tubular secretion and, in part, the excretion of tenofovir and cidofovir through the kidneys. Therefore, the pharmacokinetics of drugs that are also excreted by the kidneys, including hOAT transport proteins 1 and 3 or MRP4, may be altered if used concomitantly. Unless absolutely necessary, concomitant use of drugs that are excreted by the same renal tract is not recommended. If such use cannot be avoided, renal function should be monitored weekly (see section “Interaction with other medicinal products”).
Renal dysfunction
The safety of tenofovir with respect to renal function has been studied to a very limited extent in patients with impaired renal function (CK < 80 ml/min).
Adult patients with a KC < 50 mL/min, including patients requiring hemodialysis
Tenofovir has limited safety and efficacy data in patients with impaired renal function. For this reason, tenofovir should be used only if the potential benefits of treatment exceed the potential risks. The use of tenofovir in patients with severe impaired renal function (CK <30 ml/min) and patients who require hemodialysis is contraindicated.
Bone effects
In a controlled 144-week clinical trial comparing tenofovir with stavudine in combination with lamivudine and efavirenz among HIV-infected adults who had not previously received antiretroviral treatment, both groups showed small reductions in MPC of the femur and spine. The decrease in spinal BMD and changes from baseline in bone metabolism biomarkers were significantly more pronounced in the tenofovir group at 144 weeks. The decrease in femoral IPC was significantly more pronounced in this group up to 96 weeks. However, after 144 weeks there was no increase in fracture risk or evidence of clinically significant bone abnormalities.
Bone abnormalities (occasionally leading to fractures) may be due to damage to the proximal tubules of the kidneys (see section “Adverse effects”). If bone abnormalities are suspected or detected, the appropriate specialist should be consulted.
Effects on renal function and bone tissue in children from 12 to 18 years of age
The long-term effects on bone tissue and toxic effects on the kidneys in children have not been definitively established. In addition, the reversibility of the toxic effects on the kidneys has not been fully established. Therefore, a multifaceted approach is recommended to adequately determine the benefit/risk ratio of treatment in each individual case, decide on appropriate follow-up during treatment (including deciding whether to withdraw therapy), and consider the appropriateness of additional medications.
Renal function monitoring
Pre-treatment renal function (CK and serum phosphate levels) should be assessed, and monitoring during treatment should be performed as for adults (see above).
Management of patients with impaired renal function
If any pediatric patient receiving tenofovir has a serum phosphate level of < 3.0 mg/dL (0.96 mmol/L), renal function assessment should be repeated within 1 week, including determination of blood glucose, blood potassium and urinary glucose concentrations. If renal impairment is suspected or detected, a nephrologist should be consulted to consider whether tenofovir treatment should be discontinued.
Discontinuation of tenofovir treatment should also be considered if there is a progressive decline in renal function when no other cause has been identified.
Co-administration and risk of nephrotoxicity
The same recommendations that apply to adults (see above) must be followed.
Renal dysfunction
Tenofovir is not recommended for use in children with impaired renal function (see section “Dosage and administration”). Therapy with tenofovir should not be initiated in children with renal impairment and treatment should be discontinued in pediatric patients who develop renal impairment during tenofovir therapy.
Effects on bone tissue
Tenofovir may cause a decrease in BMD. The effect of tenofovir-related changes in BMD on bone in the long term and on future fracture risk is currently unknown (see section “Pharmacodynamics”). An endocrinologist and/or nephrologist should be consulted if bone disease is detected or suspected in children.
Liver disease
There is very little data regarding safety and efficacy in patients after liver transplantation.
The data regarding the safety and efficacy of tenofovir for patients with chronic hepatitis B, with decompensated cirrhosis and Child-Pugh grade > 9, are limited. Such patients may have a higher risk of serious adverse hepatic and renal reactions. As a consequence, hepatobiliary parameters and renal function should be carefully monitored in this patient population.
Hepatitis exacerbations
Spontaneous exacerbations of chronic hepatitis B are relatively common and are characterized by a temporary increase in serum ALT levels. After initiation of antiviral treatment, serum ALT levels may increase in some patients (see section “Side effects”). In patients with compensated liver disease, an increase in serum ALT is usually not accompanied by an increase in serum bilirubin concentration or decompensation of liver function.
Patients with cirrhosis may have an increased risk of liver function decompensation after an exacerbation of hepatitis, so they should be closely monitored during treatment.
An exacerbation after discontinuation of treatment
Hepatitis exacerbations have also been reported in patients who discontinued hepatitis B therapy. Exacerbations after discontinuation of therapy are usually associated with elevated hepatitis B DNA concentrations, and most resolve without additional interventions. However, severe exacerbations, including deaths, have been reported. For 6 months after discontinuation of hepatitis B treatment, liver function should be monitored regularly for clinical and laboratory parameters. Resumption of hepatitis B treatment may be advisable, if necessary.
In patients with advanced liver disease or with cirrhosis, discontinuation of treatment is not recommended, since exacerbation of hepatitis after discontinuation of therapy may lead to decompensation of liver function.
In patients with decompensated cirrhosis, exacerbation of hepatitis is especially serious and sometimes fatal.
Co-infection with hepatitis C or D viruses
There are no data regarding the effectiveness of tenofovir in patients with co-infection with hepatitis C or D virus.
Co-infection with HIV-1 and hepatitis B virus
Due to the risk of developing HIV resistance in patients with co-infection with HIV/HBV, tenofovir should only be used as part of an appropriate antiretroviral combination regimen.
Patients with a history of liver pathology, including chronic active hepatitis, have an increased incidence of liver function abnormalities during combination antiretroviral therapy and should be monitored according to standard practice.
If the course of liver disease worsens in such patients, consideration should be given to whether treatment should be interrupted or withdrawn. However, it should be noted that elevated ALT levels may be part of a positive HCV antiviral response to tenofovir therapy, see “Hepatitis exacerbation” above.
Lactoacidosis
Lactoacidosis, usually accompanied by fatty liver dystrophy, has been reported with nucleoside analogues.
Preclinical and clinical data suggest that the risk of lactoacidosis as an effect of nucleoside analogues is low for tenofovir. But because tenofovir is structurally similar to nucleoside analogues, this risk cannot be excluded.
Early signs (symptomatic hyperlactatemia) include mild digestive symptoms (nausea, vomiting and abdominal pain), nonspecific malaise, loss of appetite, weight loss, respiratory symptoms (rapid and/or deep breathing) or neurological symptoms (including motor weakness).
Lactoacidosis has a high mortality rate and may be accompanied by pancreatitis, hepatic or renal failure. Lactoacidosis usually occurs after several months of treatment.
The treatment with nucleoside analogues should be discontinued in the presence of symptomatic hyperlactatemia and metabolic/lactic acidosis, progressive hepatomegaly or rapid increase in aminotransferases.
Caution should be exercised when prescribing nucleoside analogues in any patient (especially obese women) with hepatomegaly, hepatitis, or other known risk factors for liver disease and fatty liver dystrophy (including certain medications and alcohol).
Treatment with interferon-alpha and ribavirin in patients with co-infection with hepatitis C virus may pose special risks.
Patients at increased risk should be closely monitored.
Lipodystrophy
In patients with HIV infection, combination antiretroviral therapy has been associated with redistribution of body fat (lipodystrophy).
The long-term effects of these phenomena are currently unknown. Data on the mechanism of development are incomplete. There is a hypothesis that the development of visceral lipomatosis is related to the intake of protease inhibitors and the development of lipoatrophy to the intake of nucleoside reverse transcriptase inhibitors.
The increased risk of lipodystrophy was due to individual factors, such as the elderly age of patients, and drug-related factors, such as long duration of antiretroviral therapy and resulting metabolic disturbances.
The clinical examination should include assessment of physical signs of body fat redistribution. Attention should be paid to fasting serum lipid values and blood glucose levels. Dyslipidemia should be corrected according to clinical guidelines.
Tenofovir is structurally related to nucleoside analogues, so the risk of lipodystrophy cannot be excluded. However, 144-week data from HIV-infected patients who were not previously treated with antiretrovirals indicate that the risk of lipodystrophy was lower with tenofovir than with stavudine when they were used in combination with lamivudine and efavirenz.
Mitochondrial disorders
In vitro and in vivo, nucleoside and nucleotide analogues have been shown to cause mitochondrial damage to varying degrees. There have been reports of the development of mitochondrial abnormalities in HIV-negative neonates exposed intrauterine and/or postnatally to nucleoside analogues.
The main adverse events reported were hematological disorders (anemia, neutropenia) and metabolic disorders (hyperlactatemia, hyperlipasemia). These phenomena were often of a short-term nature. There have been reports of some neurological abnormalities that started later (hypertension, seizures, abnormal behavior).
To date, it is unknown whether the neurological abnormalities are temporary or permanent. All children exposed intrauterine to nucleoside or nucleotide analogues, even HIV-negative newborns, should be closely monitored clinically and laboratory and screened for possible mitochondrial abnormalities if they show relevant signs or symptoms. The available data do not affect current national recommendations that HIV-positive pregnant women should receive antiretroviral therapy to prevent vertical transmission of HIV.
Immune reconstitution syndrome
In the initiation of antiretroviral therapy in HIV-infected patients with severe immunodeficiency, an inflammatory response to pathogens of asymptomatic or residual opportunistic infections may occur and result in severe clinical conditions or increased severity of symptoms. These reactions are usually seen within the first few weeks of treatment initiation.
Examples include cytomegalovirus retinitis, generalized and/or focal mycobacterial infections and Pneumocystis jirovecii pneumonia. Any symptoms of inflammation should be monitored and treatment administered promptly if necessary.
Autoimmune diseases (such as Graves’ disease) have also been reported to accompany immune reactivation; however, data on the time of onset vary widely, and these cases may have occurred several months after treatment initiation.
Osteonecrosis
While the etiology of osteonecrosis is considered multifactorial (including glucocorticosteroid use, alcohol use, presence of severe immunosuppression, higher body mass index), cases of osteonecrosis have been reported particularly frequently in patients with advanced HIV infection and/or with long-term antiretroviral combination therapy. Patients should be advised to seek medical advice if they experience joint stiffness or pain, stiffness in the joints, or difficulty moving.
Patients in the elderly
Tenofovir has not been studied in patients over 65 years of age. Elderly patients are more likely to have impaired renal function, so caution should be exercised when treating elderly patients with tenofovir.
There have been no specific studies of the effect of tenofovir on the ability to operate motor vehicles and use machinery. Patients should be informed about the presence of reports of dizziness during treatment with tenofovir. If dizziness occurs, refrain from performing the specified activities, on the ability to drive vehicles and operate machinery.
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Contraindications
– Hypersensitivity to the active ingredient or any other component of the drug.
– Children under 12 years of age and body weight < 35 kg (effectiveness and safety have not been established).
– Children 12 to 18 years of age with impaired renal function (no dosing recommendations).
– Severe renal failure (CKR < 30 ml/min) or CKD when hemodialysis is necessary (safety not established in this patient population).
– Period of lactation.
– Concurrent use with other drugs containing tenofovir,
– Concurrent use with adefovir.
– In patients with lactase deficiency, lactose intolerance, glucose-galactose malabsorption.
– In patients with diabetes mellitus; in elderly patients (over 65 years of age).
– In patients with impaired renal function (see “Special Indications”).
– In patients concomitantly taking other drugs: Those with nephrotoxic effects (aminoglycosides, amphotericin B, foscarnet, ganciclovir, pentamidine, vancomycin, interleukin-2, cidofovir); tacrolimus, nonsteroidal anti-inflammatory drugs; HIV protease inhibitors enhanced with ritonavir or cobicistat;
– In patients with a history of liver disease, including hepatitis.
– Coadministration of tenofovir and didanosine is not recommended.
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Side effects
Summary of Safety Profile
HIV-1 and Hepatitis B
Rarely, renal dysfunction, renal failure and proximal tubulopathy (including Fanconi syndrome), sometimes leading to bone pathology (rarely to fractures), have been reported in patients taking tenofovir. For patients taking tenofovir, monitoring of renal function is recommended.
HIV-1
Some adverse reactions when treated with tenofovir in combination with other antiretroviral drugs can be expected in nearly one-third of patients. These reactions are usually mild to moderate gastrointestinal abnormalities. Approximately 1% of patients treated with tenofovir have discontinued treatment because of gastrointestinal reactions.
Lactoacidosis, hepatomegaly with fatty dystrophy, and lipodystrophy have been associated with tenofovir administration.
The concomitant use of tenofovir and didanosine is not recommended because it may increase the risk of adverse reactions.
Rarely, cases of pancreatitis and lactoacidosis have been reported, sometimes with a fatal outcome.
Hepatitis B
An adverse reaction when taking tenofovir can be expected in almost one-quarter of patients, mostly minor. In clinical trials involving HBV-infected patients, the most common adverse reaction to tenofovir was nausea (5.4%). Cases of hepatitis B exacerbation have been reported in patients against the background of therapy, as well as in patients who discontinued hepatitis B treatment.
Summary of Adverse Reactions
The evaluation of adverse reactions to tenofovir is based on safety data from clinical trials and post-registration analysis. All adverse reactions are listed in Table 1.
HIV-1 Clinical Trials
The assessment of adverse reactions from the HIV-1 clinical trials is based on data from two studies in which 653 previously treated patients took tenofovir (n = 443) or placebo (n = 210) in combination with other antiretrovirals for 24 weeks, and on data from a double-blind comparative controlled trial in which 600 previously untreated patients took 300 mg tenofovir disoproxil fumarate (n = 299) or stavudine (n = 301) in combination with lamivudine and efavirenz for 144 weeks.
Hepatitis B clinical trials
. The evaluation of adverse reactions from hepatitis B clinical trials is primarily based on the results of two double-blind, comparative controlled trials in which 641 patients with chronic hepatitis Vis compensated liver function received 300 mg tenofovir disoproxil fumarate daily (n = 426) or adefovir dipivoxil 10 mg daily (n = 215) for 48 weeks. The adverse reactions observed during the 288-week uninterrupted treatment period were consistent with the known safety profile of tenofovir.
Patients with decompensated liver disease
The safety profile of tenofovir in patients with uncompensated liver disease was evaluated in a double-blind, active-controlled study in which adult patients received tenofovir (n = 45) or emtricitabine + tenofovir (n = 45), or entecavir (n = 22) for 48 weeks.
In the tenofovir group, 7% of patients discontinued treatment because of adverse reactions; 9% of patients had a confirmed elevated serum creatinine > 0.5 mg/dL or a confirmed serum phosphate concentration < 2 mg/dL at 48 weeks; there were no statistically significant differences between the tenofovir-based combination treatment group and the entecavir group.
After 168 weeks, 16% (7/45) of patients in the tenofovir group, 4% (2/45) in the emtricitabine + tenofovir group, and 14% (3/22) in the entecavir group had poor tolerability. 13% (6/45) of patients in the tenofovir group, 13% (6/45) of the emtricitabine + tenofovir group, and 9% (2/22) of the entecavir group had a confirmed elevated serum creatinine > 0.5 mg/dL or a confirmed serum phosphate concentration < 2 mg/dL.
At week 168 in this population of patients with decompensated liver failure, the mortality rate was 13% (6/45) in the tenofovir group, 11% (5/45) in the emtricitabine + tenofovir group, and 14% (3/22) in the entecavir group. The proportion of hepatic cell cancer was 18% (8/45) in the tenofovir group, 7% (3/45) in the emtricitabine + tenofovir group, and 9% (9/22) in the entecavir group.
Patients with a baseline high Child-Pugh score had a greater risk of serious adverse reactions (see “Special Considerations”).
Patients with HBV resistance to lamivudine
In a randomized, double-blind study in which 280 lamivudine-resistant patients received tenofovir (n = 141) or emtricitabine/tenofovir (n = 139) for 96 weeks, no new adverse reactions were identified.
The adverse reactions with a potential (or at least possible) link to treatment are listed below by organ system class and frequency. Within each frequency group, adverse reactions are listed in decreasing order of severity.
The adverse reactions by frequency are defined as: very common (≥ 1/10), common (≥ 1/100 to < 1/10), infrequent (≥ 1/1000 to < 1/100), and rare (≥ 1/10,000 to < 1/1000).
Table 1. Summary of adverse reactions associated with tenofovir administration based on clinical studies and post-registration analysis
Organ system classes and frequency | Adverse reactions | ./tr> | |
Metabolic and nutritional disorders | |||
Very common | Hypophosphatemia1 | ||
Infrequent | Hypokalemia1 | ||
Rarely | Lactoacidosis3 | ||
colspan=”2″> Nervous system disorders | |||
Very often | Dizziness | ||
Often | Headache | ||
Gastrointestinal tract disorders | |||
Very often | Diarrhea, vomiting, nausea | ||
often | Abdominal pain, bloating, flatulence | ||
Infrequent | Pancreatitis3 | ||
Disorders of the liver and biliary tract /p> | |||
Often | Increased “hepatic” transaminase activity | ||
Rarely | Fatty liver dystrophy 3, hepatitis | ||
Skin and subcutaneous tissue disorders /p> | |||
Very often | Skin rash < | ||
Rarely | Angioedema < | ||
Muscular and connective tissue disorders | |||
Skeletal and connective tissue disorders/p> | |||
Infrequent | Rhabdomyolysis1, muscle weakness1 | ||
Rarely | Osteomalacia (manifested by bone pain and bone fractures in some cases)1,2, myopathy1 | ||
Renal and urinary tract disorders | |||
Infrequent | Elevated creatinine | ||
Rarely | Acute renal failure, renal failure, acute tubular necrosis, proximal renal tubulopathy (including Fanconi syndrome), nephritis (including acute interstitial nephritis)2, nephrogenic non-sugar diabetes | ||
General disorders and disorders at the site of administration | |||
Very often | Asthenia | ||
Often | Fatigue |
Weight | 0.035 kg |
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Shelf life | 4 years. Do not use after the expiration date. |
Conditions of storage | In the dark place at a temperature not exceeding 25 °С. Store out of the reach of children. |
Manufacturer | Pharmasintez JSC, Russia |
Medication form | pills |
Brand | Pharmasintez JSC |
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