Fovirpoxil OPV Tenofovir Disoproxil Fumarate treatment for hepatitis B, HIV-1 (3 blisters x 10 tablets)

ATC code: J05AF07

Mechanism of action

Tenofovir disoproxil fumarate is the Fumarate salt of Tenofovir Disoproxil. Tenofovir Disoproxil is absorbed and converted into Tenofovir activity, a substance similar to nucleoside monophosphate (nucleotide). Tenofovir is then converted into metabolites with tenofovir diphosphate, by enzymes in the cell. Tenofovir diphosphate has a 10 -hour intracellular sale period in activated cells and 50 hours in mononerosocyte cells of foreign blood (PBMCS). Tenofovir diphosphate inhibits the enzyme copying HIV-1 and HBV Polymerase by competing directly with the natural substrate Deoxyribonucleotide and, after merging DNA, by the end of the DNA chain. Tenofovir diphosphate is a weak inhibitor of cell polymerase A, B, and Y. At a concentration of up to 300 PMOL/L, Tenofovir shows no effect on the synthesis of mitochondrial DNA or lactic acid production in Vitro quantitative quantification.

HIV -related data

Antibiotic HIV in vitro:

Tenofovir concentration is needed to inhibit 50% (EC ,,) of HIV-1B wild experimental strain is 1-6 umol/l in lymph cell lines and is 1.1 umol/l for the majority of HIV-1 isolation strains in PBMCS. Tenofovir also has HIV-1, Group A, C, D, E, E, G, and O and HIV and HIV in mononocular leukocytes. Tenofovir shows that there is HIV-2-resistant in vitro activity, with EC, 4.9 umol/l in MT-4 cells.

resistance:

HIV-1 strains are sensitive to the decreased and mutant Tenofovir K65R in the reverse copy enzyme selected in vitro and in some patients. Tenofovir disoproxil fumarate should be avoided for patients who have treated Retrovirus resistance due to viral infection with K65R mutation. In addition, a K70E replacement in the HIV-1 copy code was selected by Tenofovir and the result was to reduce the sensitivity to Tenofovir at a low level.

Clinical studies in patients who have been treated for HIV anti-HIV activity of Tenofovir Disoproxil 245 mg (Fumarate form) for HIV-1 strains are resistant to nucleoside inhibitors. The results show that patients infected with HIV strains contain up to 3 or more mutations related to the same substance as Thymidine (Tam) including mutations in the enzyme copied backwards or M41L or L210W showing a decrease in response to the Tenofovir disoproxil 245mg regimen.

Dynamic pharmacokinetics

tenofovir disoproxil fumarate is an ester -soluble medicine in water and quickly converted in vivo into tenofovir and formaldehyde.

Tenofovir is converted in intracellular to Tenofovir Monophosphate and into a substance with the active substance Tenofovir Diphosphate.

absorption

After taking the dose of Tenofovir Disoproxil Fumarate in HIV -infected patients, Tenofovir Disoproxil Fumarate is quickly absorbed and transformed into Tenofovir. Use multi -dose Tenofovir disoproxil fumarate with food in HIV -infected patients for the results of the average value of Tenofovir (%CV) CMAX. The maximum concentration of tenofovir is observed in the serum for 1 hour after drinking and 2 hours after drinking with food. Tenofovir's oral bioavailability from Tenofovir Disoproxil Fumarate in patients with hunger is about 25%

Taking Tenofovir Disoproxil Fumarate with a high -fat meal that increases the oral bioavailability of the drug, of which Tenofovir's AUC increases by 40% and CMAX increases by about 14%. When the patient is taken for the first dose of Tenofovir Disoproxil Fumarate at the time of full food, the average annual cmax value is between 213 to 375 ng/ml. However, taking Tenofovir Disoproxil Fumarate and a snack does not significantly affect the pharmacokinetics of Tenofovir.

Distribution

After intravenous transmission, the distribution volume in the stable state of Tenofovir is estimated to be about 800 ml/kg. After taking Tenofovir Disoproxil Fumarate, Tenofovir is distributed in most tissues, with the highest concentration in the kidney, liver and intestinal tract (according to preclinical studies). In vitro the level of cohesion to plasma or serum protein is below 0.7 and 7.2%, with Tenofovir concentration in the range of 0.01 to 25 ng/ml. Metabolism:

In vitro studies have identified that both tenofovir disoproxil fumarate and tenofovir are not the substrate for the enzyme CYP450. Moreover, at significantly higher concentrations (about 300 times) compared to the observation in vivo, Tenofovir does not inhibit the metabolism of in vitro through intermediaries any part of CYP450 isomers related to the biological shift (CYP3A4, CYP2D6, CYP2C9, CYP2E1 or CYP1A1/2). At a concentration of 100 Ug/ml, Tenofovir Disoproxil Fumarate does not work on any CYP450 isomer, except for CYP1A1/2, which has observed a small part (6%) decreased with statistical significance in the metabolism of CYP1A1/2 substrate. Based on these data, there is almost no significant clinical interaction between Tenofovir Disoproxil Fumarate and metabolic drugs through the CYP450 system.

Elimination

Tenofovir is excreted mainly through the kidneys with both dialysis and through the active transportation system in the renal tubules with about 70 - 80% understood excretion in the urine in the form of unchanged when using intravenous tract. Estimated about 230 ml/hour/kg (about 300 ml/minute). The renal clearance is estimated at about 160 ml/hour/kg (about 210 ml/min), exceeding the filtration rate in the glomerular. This indicates that the active excretion through the renal tubules is an important part of the elimination of tenofovir. Tenofovir waste sale time when used orally is about 12 - 18 hours. Studies have shown the active excretion through the renal tubules of Tenofovir into the renal tubular cell near by human organic anions (media) 1 and 3 and escape urine with MRP4.

Linear/non -linear:

Tenofovir pharmacokinetics does not depend on the dose of Tenofovir Disoproxil Fumarate in the dose range from 75 to 600 mg and is not affected when the dose is repeated at any dose.

Age:

Dynamic studies have not been conducted in the elderly (over 65 years old).

Sex:

Tenofovir's limited data on pharmacokinetics in women indicates that there is no great influence of gender.

Race:

There are no specific studies on pharmacokinetics in different racial groups. Child population:

HIV-1: Mobile pharmacokinetics in a stable state of Tenofovir are assessed in 8 HIV-1 teenagers (from 12 to under 18 years old) with weight ≥ 35 kg. The average values ​​(± sd) CMR and AUC corresponding to 0.38 ± 0.13 ng/ ml and 3.39 ± 1.22 pgs/ ml. Tenofovir exposure is achieved in teenagers after using the doses of Tenofovir Disoproxil 245 mg (Fumarate form) by oral daily similar to the exposure achieved in adults after using the doses of Tenofovir disoproxil 245 mg (Fumarate form) once a day.

Chronic hepatitis B: Tenofovir exposure in a stable state in HBV teenage patients (12 to under 18 years old) after using a dose of Tenofovir Disoproxil 245 mg (Fumarate form) once a day is similar to the exposure achieved in adult patients using Tenofovir Disoproxil 245 mg (Fumarate) once a day. Pharmacokinetics tests are not done in children under 12 years old or with kidney failure.

Renal failure: Tenofovir pharmacokinetics indicators are determined after taking a single dose of Tenofovir disoproxil 245 mg per HIV-infected adult patients, HBV has different levels of renal failure, determined based on the initial creatinine clearance (CRCl) (kidney function is normal if the CRCL> 80 mL/minute; CRC1 = 30-49 ml/min and heavy with CrCl = 10-29 ml/minute). Compared to patients with normal renal function, the average level of Tenofovir exposure (%CV) has increased from 2185 (12%) of the year/ml in objects with CrCl> 80 ml/min, respectively 3064 (30%) of the year/ml, 6009 (42%) Ngam/mL and 15985 (45%) The recommended dose for patients with renal failure, with an increase in the distance between two use, is expected to produce higher peak plasma concentrations and lower CMAX levels in patients with renal impairment than patients with normal renal function. Its clinical relevance is still unknown.

In patients with end -stage kidney disease (ESRD) (CrCl

Recommendations to adjust the distance between two uses Tenofovir Disoproxil 245 mg (Fumarate form) in adult patients with creatinine clearance

Hepatic failure:

A single dose of Tenofovir Disoproxil 245 mg is used for non-HIV-infected adults, HBV has different levels of liver failure determined in the way of classification of Child-Pugh-Turcotte (CPT). The pharmacokinetics of Tenofovir are actually not changed in subjects with liver failure, which suggests that the dose is no need to adjust in these patients. The average values ​​of Tenofovir concentration (%CV) C and AUC are 223 (34.8%) ng/ml and 2050 (50.8%) from the normal liver function patients, compared to 289 (46.0%) ng/ml and 2310 (43.5%) in patients with average liver impairment and 305 (24.8%). W/ml in patients with severe liver failure. Hypermathy pharmacokinetics:

In the non -reproductive single blood cells in the peripheral blood of the person (PBMC), Tenofovir Diphosphate's disposal time is about 50 hours, while the sale time in PBMC cells is stimulated by phytohaemaglutinin is about 10 hours.

This unwanted reaction was determined in post -commercial surveys but did not observe in randomized clinical tests or in the expanded patient support program using Tenofovir Disoproxil Fumarate. The frequency is estimated from the statistical calculation based on the total number of exposure patients with Tenofovir Disoproxil Fumarate in random clinical tests and expanding patient support programs. Immediately notify the doctor or pharmacist the harmful reactions encountered when using the drug.

Be cautious when using drugs

need to take HIV antibodies for all HBV infected patients before starting treatment with Tenofovir Disoproxil Fumarate.

HIV-1: Although the effective inhibition of viruses with Retrovirus resistance has been shown to significantly reduce the risk of sexual transmission, it is not possible to eliminate the risk of remaining. Preventive measures to prevent infection should be taken in accordance with national instructions.

Chronic hepatitis B:

Advise patients that Tenofovir Disoproxil Fumarate has not been shown to prevent the risk of HBV spreading through sex or blood infected blood. Need to continue using other preventive measures.

Concentrated with other drugs: Fovirpoxil should not be used simultaneously with other drugs containing Tenofovir Disoproxil Fumarate or Tenofovir Alafenamide. Do not use fovirpoxil simultaneously with adefovir dipivoxil.

There is no recommendation to share tenofovir disoproxil fumarate and didanosine. Simultaneous use of Tenofovir Disoproxil Fumarate and Didanosine increases the system exposure to DIDANOSINE 40-60% that can increase the risk of unwanted effects related to Didanosine. Rarely, pancreatitis and acidic acidic acid, sometimes death, have been reported. Simultaneous use of tenofovir disoproxil fumarate and didanosine at a dose of 400 mg per day is related to a significant reduction in the number of CD4 cells, which may be due to intracellular interaction that increases the phosphorylation (active) of didanosine. The reduction of the 250 mg of Didanosine is simultaneously used with Tenofovir Disoproxil Fumarate related to reports on high anti-virus failures in many combinations to treat HIV-1 infection.

Treatment regimen combines 3 nucleoside/nucleotides:

There have been reports on high rate of failure in antivirus and remarkable drug resistance in the early stage in HIV patients when Tenofovir Disoproxil Fumarate is combined with Lamivudine and Abacavir as well as combined with Lamivudine and Didanosine in the one -day regimen.

Effects in the kidneys and adult bones:

Effects in the kidney: Tenofovir is excreted mainly through the kidneys. Renal failure, kidney failure, increased creatinine, reduced blood phosphate and kidney tubulopathy (including fanconi syndrome) have been reported with the use of Tenofovir Disoproxil Fumarate clinically.

Kidney monitoring: It is recommended that the creatinine clearance is calculated in all patients before starting treatment with Tenofovir disoproxil fumarate and renal function (creatinine and serum phosphate) are also monitored after 2-4 weeks of treatment, after three months of treatment and every three to six months in patients with no kidney risk factors. In patients at risk of kidney failure, renal function is needed more often.

Renal disease management: If serum phosphate

Simultaneous use and the risk of kidney poisoning

Avoid using Tenofovir Disoproxil Fumarate simultaneously or recently with a kidney toxic drug (such as Aminoglycosides, Amphotericin B, Foscarnet, Ganciclovir, Pentamidine, Vancomycin, Cidofovir or Interleukin-2). If using Tenofovir Disoproxil Fumarate simultaneously and kidney toxic drugs are inevitable, should check the weekly kidney function.

Cases of acute renal failure after taking a high starting dose or many nonsteroidal anti -inflammatory drugs (NSAIDs) have been reported in patients treated with tenofovir disoproxil fumarate and have risk factors for kidney dysfunction. Need to check adequate kidney function when using Tenofovir Disoproxil Fumarate simultaneously with an nonsteroidal anti -inflammatory drug (NSAID).

Tenofovir disoproxil fumarate has not been clinically evaluated in patients who are taking excreted drugs through the same kidney system, including organic anion transport system transporting protein in humans (media) 1 and 3 or MRP 4 (such as Cidofovir is a known kidney toxic substance). These renal transport proteins can be responsible for the excretion in the renal tubules, and partly, in eliminating the kidneys of Tenofovir and Cidofovir. Therefore, the pharmacokinetics of these drugs, which is excreted through the same kidney path, including active and 3 or 3 or MRP 4 transport proteins, may be changed if they are used simultaneously. Unless it is necessary, it is not recommended to simultaneously use these drugs, but they are excreted through the same kidney path, but if used so is inevitable, should monitor kidney function every week.

Renal failure: Kidney safety with Tenofovir Disoproxil Fumarate is only studied at a limited level in adult patients with impaired renal function (Creatinine clearance

Adults have creatinine clearance

Data on safety and effectiveness of tenofovir disoproxil fumarate in patients with impaired renal function is limited.

Effects on the bone: In HIV -infected patients, in a 144 -week controlled clinical study compares Tenofovir Disoproxil Fumarate with Stavudine in the formula combined with Lamivudine and Efavirenz in adult patients who have never treated Retrovirus resistance, observing a slight decrease in bone density (BMD) At 144 weeks, the decrease in bone density in the spine and transforms bone biological signs compared to the beginning of research in the Tenofovir Disoproxil Fumarate treatment group significantly greater than the other group. In this group, the reduction of bone density in the hip is also significantly greater than the other group until the 96th week. However, after 144 weeks of treatment, there is no increased risk of fracture or clinical evidence of bone abnormalities.

In other studies (advancing and crossing), the most obvious BMD reduced in patients treated with Tenofovir Disoproxil Fumarate as part of the protease inhibitor treatment regime. Alternative therapies should be considered for patients with high risk of osteoporosis.

Bone abnormalities (not often causing fractures) may be related to near -renal tubulopathy.

Should consult a doctor if suspected or discovered with bone abnormalities.

Kidney and bone effects in children:

Not sure about long -term effects on bones and kidney toxicity. Moreover, the recovery of toxicity on the kidneys cannot be fully determined. Therefore, the multidisciplinary approach is recommended to fully assess each case of balance between benefits/risk of treatment, appropriate monitoring decisions during treatment (including decision to stop treatment) and consider the necessity of additional measures.

Kidney effects: Unwanted reactions in the kidneys in accordance with the renal tubulopathy have been reported in HIV-1 infected patients from 2 to 12 years old in clinical research.

Kidney monitoring: Renal function (Creatinine clearance and serum phosphate) should be evaluated before treatment and monitoring during treatment as in adults.

Kidney management: If the serum phosphate is confirmed as If suspected or detecting kidney abnormalities, you should consult a kidney specialist to consider interrupting treatment with Tenofovir disoproxil fumarate. Interrupt treatment with Tenofovir Disoproxil Fumarate should also be considered in the event of a renal function progression without finding any other cause.

Concomitance and risk of kidney toxicity: Similar recommendations are applied as in adults.

Renal failure: Do not use Tenofovir Disoproxil Fumarate in children with body failure. Tenofovir Disonroxil Fumarate The treatment with Tenofovir Disoproxil Fumarate.

Effects on bone: Fovirpoxil may reduce bone density (BMD). The effect of changes related to Tenofovir Disoproxil Fumarate on BMD on long -term bone health and the risk of future fractures is not known.

If you detect or suspect bone abnormalities in children, should consult with endocrine experts and/ or kidney experts.

Liver disease

data on safety and effectiveness is very limited in liver transplant patients.

Data on safety and effectiveness of tenofovir disoproxil fumarate in HBV infected patients with unslaced liver disease and child-pug-turcotte scores (CPT)> 9 are limited. These patients may be at risk of reaction; Want serious liver and kidneys higher. Therefore, the parameters of the liver and kidneys must be closely monitored in this patient group.

Severe hepatitis

Outbreaks in the treatment: Spontotive outbreaks in chronic hepatitis B are relatively common and are characterized by increased serum ALT. After starting treatment with antiviral drugs, serum alt may increase in some patients. In patients with compensation liver disease, the increase in serum ALT is often not accompanied by increased serum bilirubin concentration or liver loss. Patients with cirrhosis may be at risk of liver loss due to severe hepatitis, thus need to be closely monitored during treatment.

Outbreak after treatment: Acute severe hepatitis has also been reported in patients who have stopped treating hepatitis B B. Serious after treatment often accompanied by HBV DNA, and most seemed to be limited. However, serious serious waves, including death, have been reported. The liver function must be monitored for repeated periods with both clinical monitoring and tests for at least 6 months after the treatment of hepatitis B. If appropriate can continue the treatment of hepatitis B B. In patients with progressive liver disease or cirrhosis, it is not recommended to stop treatment because of serious hepatitis after treatment can lead to liver loss.

Liver outbreaks are particularly serious and sometimes fatal in patients with liver disease.

co -infected with hepatitis C or D: There is no data on the effectiveness of Tenofovir in patients with the co -infection of the hepatitis C or D virus.

co-infected with HIV-1 and hepatitis B: Due to the risk of HIV resistance development, Tenofovir Disoproxil Fumarate should only be used in part of a suitable Retrovirus resistance regimen in HIV/HBV co-infected patients.

Patients with previous liver dysfunction, including active chronic hepatitis, have abnormal increased liver function frequency in the combination of Retrovirus anti -Retrovirus and should be monitored. If there are evidence of more severe liver disease in these patients, interrupting or stopping treatment must be considered. However, it should be noted that increasing ALT can be part of HBV clearing during treatment with tenofovir.

Use with some antiviral antiviral drugs

Using Tenofovir Disoproxil Fumarate along with Ledipasvir/Sofosbuvir or Sofosbuvir/Velpatasvir shows increased consistency of plasma tenofovir, especially when used with HIV treatment regimen containing Tenofovir Disoproxil Fumarate and hyperactive drug enhancement (Ritonavir or Coobicistat). The safety of Tenofovir Disoproxil Fumarate in the arrangement of Ledipasvir/Sofosbuvir or Sofosbuvir/Velpatasvir and a kinetic enhancement has not been set.

Potential risks and benefits related to simultaneous use with Lidopasvir/Sofosbuvir or Sofosbuvir/Velpatasvir with Tenofovir Disoproxil Fumarate used with a Protease HIV inhibitor (such as Atazanavir or Darunavir) should be considered, especially in patients with kidney disorder risks. Need to monitor unwanted reactions related to Tenofovir Disoproxil Fumarate in patients with simultaneous use of Ledipasvir/Sofosbuvir or Sofosbuvir Velpatasvir with Tenofovir Disoproxil Fumarate and an enhanced HIV protease inhibitor.

Weight and metabolic parameters: weight gain, lipid gain and blood glucose may occur during the treatment of Retrovirus. Such changes may be related to disease control and lifestyle. For lipids, there are several cases of evidence of the effectiveness of treatment, while for weight gain, there is no strong evidence related to any special treatment. To monitor lipids and blood glucose reference is evaluated to set HIV treatment guidelines. Lipid disorders should be appropriate clinical management.

Mitochondrial dysfunction after the uterus:

Similar substances nucleoside and nucleotide can affect the function of mitochondria to a different level, most noted with Stavudine, Didanosine and Zidovudine.

There have been reports on mitochondrial dysfunction in HIV -negative infants who are exposed to the uterus and/or after birth with similar substances nucleoside and nucleotide; These are mainly related to treatment with zidovudine.

The unwanted reactions are mainly reported as hematological disorders (anemia, neutropenia) and metabolic disorders (hyperlactemia, hyperlase blood lipase). These events are often fleeting. Symptoms of late neurological disorders have been reported as rare (hypertension, convulsions, abnormal behaviors). Such neurological disorders are transient or permanently unknown.

These findings should be considered for any child to be exposed to the uterus with nucleoside and nucleotide substances, who have serious clinical test results without the cause, especially neurological tests. These findings do not affect the current national recommendations for the use of Retrovirus anti -Retrovirus therapy in pregnant women to prevent HIV transmission.

Immunodes of immunosuppressive syndrome

In patients with HIV infected with severe immunodeficiency at the beginning of the combination of anti -Retrovirus (Cart), an inflammatory reaction to the occasional or disadvantaged pathogens that appear and cause

Serious clinical disease or serious symptoms. Typically, these reactions are seen within a few weeks or the first few months when starting cart. For example, cytomegalovirus retinitis, bodybacterium infection with body and/or local or local and pneumonia caused by pneumocystis jirovecii. Any symptoms of inflammation should be evaluated and conducted when necessary.

Autoimmune disorders (such as Graves disease) have also been reported to occur during immunosuppressive activity, however, the time of reporting is more variance and these changes may occur months after the beginning of treatment.

Bone necrosis

Although the cause of the disease is thought to be multi -factor (including the use of corticosteroids, drinking alcohol, serious immunosuppressive inhibitors, higher body index), cases of bone necrosis have been reported, especially in patients with progressive HIV disease and/or long -term exposure to cart. Patients should advise medical advice if they have joint pain and pain, stiffness or difficulty in movement.

Elderly

Tenofovir disoproxil fumarate has not been studied in patients over 65 years old. Older patients are more likely to have renal function, so be cautious when treating elderly patients with Tenofovir Disoproxil Fumarate.

This drug contains: lactose. Patients with rare genetic problems are galactose intolerance, Lapp Lactase deficiency, or malposive glucose-galactose should not take this drug.

Using drugs for pregnant women:

Average data on pregnant women (about 300 - 1000 pregnant women) shows no deformities or toxicity in the fetus/infant related to Tenofovir disoproxil fumarate. Animal studies do not indicate reproductive toxicity. The use of Tenofovir Disoproxil Fumarate may be considered during pregnancy, if necessary.

Use medicine for breastfeeding women:

Tenofovir has been shown to be excreted through breast milk. There is no adequate information about the effects of tenofovir in infants. Therefore, you should not use fovirpoxil when breastfeeding.

The effect of drugs on driving and operating machinery

There is no research on the effect of the drug on the ability to drive, operate machinery. However, the patient should be reported to have a report on dizziness, headache, fatigue occurring when treating with Tenofovir Disoproxil Fumarate.

Drug interaction

Interactive studies are only done in adults.

Based on the results of in vitro experiments and the known excretion path of Tenofovir, the ability to interact through the CYP450 intermediaries related to Tenofovir with other drugs is low.

does not recommend simultaneously

Do not use fovirpoxil simultaneously with other drugs that contain tenofovir disoproxil fumarate or tenofovir alafenamide. Do not simultaneously use fovirpoxil with adefovir dipivoxil.

didanosine

There is no recommendation to share tenofovir disoproxil fumarate and didanosine.

Kidney elimination drugs:

Because Tenofovir is excreted mainly through the kidneys, simultaneously using Tenofovir Disoproxil Fumarate with drugs that reduce the kidney function or competition active excretion via renal tubules through activated, activated 3 or MRP 4 (such as cidofovir) can increase the level of tenofovir in plasma and/or shared drugs.

Should avoid using Tenofovir Disoproxil Fumarate at the same time or close to a toxic drug for the kidneys. Including, but unlimited, aminoglycoside, amphotericin B, foscarnet, ganciclovir, pentamidine, vancomycin, cidofovir or interleukin-2.

It is thought to be Tacrolimus that can affect kidney function, so closely monitoring when used simultaneously with tenofovir disoproxil fumarate.

Other interactions

Interaction between Tenofovir Disoproxil Fumarate and other drugs listed below:

antiviral drugs

Protease inhibitors

Atazanavir/Ritonavir (300 Q.D./100 Q.D./300 Q.D.); Lopinavir/ritonavir (400 B.I.D./100 B.I.D./300 Q.D.); Darunavir/Ritonavir (300/100 B.I.D./300 Q.D.): No dose adjustment. Increasing the risk of exposure to Tenofovir may increase side effects related to Tenofovir, including renal disorders. Should closely monitor kidney function.

NRTI

Didanosine: It is not recommended to combine Tenofovir Disoproxil Fumarate and Didanosine.

adefovir dipivoxil: Should not use Tenofovir Disoproxil Fumarate simultaneously with adefovir dipivoxil.

Entecavir: There is no significant pharmacokinetic interaction when Tenofovir Disoproxil Fumarate is used with Entecavir.

antiviral antiviral drugs C: