Virfoten, 300 mg 30 pcs

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:

The treatment of chronic hepatitis B in children aged 12 to 18 years with

Active ingredient

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 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

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

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.

(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

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

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.

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.

Side effects

Summary of Safety Profile

HIV-1 and Hepatitis B

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

Summary of Adverse Reactions

HIV-1 Clinical Trials

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

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.

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

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

Metabolic and nutritional disorders

Very common

Hypophosphatemia1

Infrequent

Hypokalemia1

Rarely

Lactoacidosis3

Nervous system disorders

Very often

Dizziness

Often

Headache

Gastrointestinal tract disorders

/p>

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

Overdose

Symptoms: in case of overdose, the patient should be monitored for signs of toxicity; if necessary, symptomatic and supportive therapy is prescribed.

Pregnancy use

Pregnancy

The data obtained from a medium-volume sample in pregnant women (300 to 1,000 pregnancy outcomes) indicate no malformations or toxic effects on the fetus/newborn that would be associated with tenofovir administration.

Animal studies have indicated no toxic effects on reproductive function. Thus, tenofovir can be considered for use during pregnancy if necessary.

Breastfeeding

Studies have shown that tenofovir is excreted in breast milk. There are insufficient data on the effect of tenofovir on newborns/infants. Therefore, tenofovir should not be used during breastfeeding.

In general, women infected with HIV and HBV are not recommended to breastfeed to avoid transmission of HIV and HBV to the baby.

Fertility

There are no data on the effect of tenofovir on fertility in humans. Studies in animals do not indicate harmful effects of tenofovir on fertility.