What are the potential side effects of Entecavir (Baraclude). How does Entecavir affect liver function and lactic acid levels. When should patients contact their doctor while taking Entecavir. What are the risks of stopping Entecavir treatment abruptly. How does Entecavir interact with HIV medications.

Understanding Entecavir: A Comprehensive Overview

Entecavir, marketed under the brand name Baraclude, is a crucial medication in the treatment of chronic hepatitis B virus (HBV) infection. As an oral nucleoside analogue, it plays a significant role in managing this persistent liver condition. However, like all medications, it comes with potential side effects and important considerations that patients and healthcare providers must be aware of.

What is Entecavir and How Does It Work?

Entecavir functions by inhibiting the replication of the hepatitis B virus in the body. By doing so, it helps reduce the viral load and mitigates damage to the liver. This medication is part of a class of drugs known as nucleoside/nucleotide analogues (NAs), which form the backbone of chronic hepatitis B treatment strategies.

Serious Side Effects: Liver Damage and Lactic Acidosis

While Entecavir is generally well-tolerated, it can potentially cause severe side effects that require immediate medical attention. Two of the most serious concerns are liver damage and lactic acidosis.

How Does Entecavir Affect Liver Function?

In some cases, Entecavir can cause serious or life-threatening damage to the liver. Patients with pre-existing liver conditions may be at higher risk. It’s crucial to monitor liver function regularly during treatment.

Understanding Lactic Acidosis Risk

Lactic acidosis, a buildup of acid in the blood, is another potential serious side effect of Entecavir. Certain factors may increase the risk of developing this condition:

• Being female
• Being overweight
• Long-term treatment with HBV medications

When Should Patients Seek Immediate Medical Attention?

Patients taking Entecavir should be vigilant for the following symptoms and contact their doctor immediately if they occur:

• Yellowing of the skin or eyes (jaundice)
• Dark-colored urine
• Light-colored bowel movements
• Difficulty breathing
• Stomach pain or swelling
• Nausea or vomiting
• Unusual muscle pain
• Loss of appetite lasting several days
• Extreme weakness or tiredness
• Feeling cold, especially in the arms or legs
• Dizziness or lightheadedness
• Fast or irregular heartbeat

The Importance of Consistent Entecavir Treatment

Maintaining a consistent treatment regimen is crucial when taking Entecavir. Abruptly stopping the medication can lead to serious consequences.

Why is it Dangerous to Stop Entecavir Suddenly?

Discontinuing Entecavir without medical supervision can cause hepatitis B to worsen, particularly in the first few months after stopping. This rebound effect can be severe and potentially life-threatening.

What Symptoms Indicate a Potential Rebound Effect?

If you’ve stopped taking Entecavir and experience any of the following symptoms, seek immediate medical attention:

• Extreme tiredness or weakness
• Nausea or vomiting
• Loss of appetite
• Yellowing of the skin or eyes
• Dark-colored urine
• Light-colored bowel movements
• Muscle or joint pain

Entecavir and HIV: Important Considerations

For patients with or at risk of HIV infection, taking Entecavir requires special consideration and monitoring.

How Does Entecavir Interact with HIV Treatment?

If a patient has untreated HIV or AIDS and takes Entecavir, it may make their HIV infection more difficult to treat in the future. Therefore, HIV testing before and during Entecavir treatment is crucial for at-risk individuals.

Why is HIV Testing Important for Entecavir Patients?

HIV testing ensures that patients receive appropriate treatment for both conditions if necessary. It’s important to note that while Entecavir treats hepatitis B, it does not treat HIV infection.

Monitoring and Follow-up: Ensuring Safe Entecavir Use

Regular medical follow-up is essential for patients taking Entecavir to ensure its effectiveness and monitor for potential side effects.

What Tests Are Necessary During Entecavir Treatment?

Patients should maintain all scheduled appointments with their healthcare provider and laboratory. These visits typically involve:

• Blood tests to monitor liver function
• Viral load tests to check HBV levels
• Kidney function tests
• HIV testing, if necessary

How Long Should Monitoring Continue?

Monitoring should continue not only during treatment but also for several months after completing Entecavir therapy. This extended observation period helps detect any delayed effects or viral rebound.

Class Effects of Nucleoside/Nucleotide Analogues

As a member of the nucleoside/nucleotide analogue class, Entecavir shares some potential side effects with other medications in this group.

What Are the Common Class Effects of NAs?

Class effects of nucleoside/nucleotide analogues can include:

• Myopathy (muscle weakness)
• Neuropathy (nerve damage)
• Lactic acidosis

Why Do NAs Carry a “Black Box” Warning?

All nucleoside/nucleotide analogues, including Entecavir, carry a “Black Box” warning due to the potential risk of mitochondrial dysfunction. This cellular-level effect can lead to various systemic issues if it occurs.

Comparing Entecavir to Other Hepatitis B Medications

While Entecavir is generally well-tolerated, it’s important to understand how its side effect profile compares to other hepatitis B treatments.

How Does Entecavir Compare to Lamivudine and Telbivudine?

Lamivudine and telbivudine, other medications used to treat hepatitis B, are associated with a higher incidence of class-related adverse effects compared to Entecavir. These effects, while rare, are more commonly reported with these older medications.

What Are the Specific Concerns with Adefovir and Tenofovir?

Adefovir, another hepatitis B medication, can cause dose- and time-dependent nephrotoxicity, even at low doses. This means it can potentially damage the kidneys over time.

Tenofovir, while effective against hepatitis B, has shown significant renal and bone toxicity in patients with HIV infection. However, these effects are less pronounced in hepatitis B patients without HIV co-infection.

Managing Entecavir Side Effects: Patient and Provider Strategies

While the potential side effects of Entecavir can seem daunting, there are strategies that patients and healthcare providers can employ to manage risks effectively.

How Can Patients Minimize Entecavir Side Effects?

Patients can take several steps to reduce their risk of experiencing adverse effects:

• Take the medication exactly as prescribed
• Maintain regular check-ups and lab tests
• Report any unusual symptoms promptly
• Maintain a healthy lifestyle, including proper diet and exercise
• Avoid alcohol and other substances that can stress the liver

What Monitoring Strategies Do Healthcare Providers Use?

Healthcare providers employ various strategies to monitor patients on Entecavir:

1. Regular liver function tests
2. Periodic kidney function assessment
3. Monitoring of lactic acid levels if symptoms suggest lactic acidosis
4. Bone density scans for long-term users
5. HIV testing when appropriate

Long-term Outlook: Living with Chronic Hepatitis B and Entecavir Treatment

Understanding the long-term implications of Entecavir treatment is crucial for patients with chronic hepatitis B.

Can Entecavir Cure Hepatitis B?

While Entecavir is highly effective at suppressing the hepatitis B virus, it is not a cure. Most patients will need to continue treatment indefinitely to maintain viral suppression and prevent liver damage.

What Is the Prognosis for Patients on Long-term Entecavir Treatment?

The long-term outlook for patients on Entecavir is generally positive. With proper adherence to treatment and regular monitoring, many patients can effectively manage their hepatitis B and prevent progression to more serious liver conditions like cirrhosis or liver cancer.

Future Directions: Research and Development in Hepatitis B Treatment

As our understanding of hepatitis B and its treatment evolves, research continues to explore new avenues for more effective and safer therapies.

What New Treatments Are on the Horizon for Hepatitis B?

Researchers are investigating several promising approaches to hepatitis B treatment:

• Novel antiviral agents with different mechanisms of action
• Immunotherapies to boost the body’s natural defenses against the virus
• Combination therapies that may offer more complete viral suppression
• Gene editing techniques to target the virus directly

How Might Future Treatments Improve Upon Entecavir?

Future treatments aim to address some of the limitations of current therapies like Entecavir:

• Potential for complete viral clearance or functional cure
• Shorter treatment durations
• Reduced risk of drug resistance
• Fewer long-term side effects
• More convenient dosing regimens

As research progresses, patients and healthcare providers can look forward to potentially more effective and safer options for managing chronic hepatitis B. However, it’s important to remember that Entecavir remains a crucial and effective treatment option for many patients today.

In conclusion, while Entecavir (Baraclude) is a powerful tool in the fight against chronic hepatitis B, it requires careful management and monitoring. Patients should maintain open communication with their healthcare providers, adhere to prescribed treatment regimens, and stay informed about their condition and medication. With proper use and regular follow-up, Entecavir can help many patients effectively manage their hepatitis B and maintain their overall health.

Entecavir: MedlinePlus Drug Information

Entecavir can cause serious or life-threatening damage to the liver and a condition called lactic acidosis (a buildup of acid in the blood). The risk that you will develop lactic acidosis may be higher if you are a woman, if you are overweight, or if you have been treated with medications for hepatitis B virus (HBV) infection for a long time. Tell your doctor if you have or have ever had liver disease. If you experience any of the following symptoms, call your doctor immediately: yellowing of the skin or eyes; dark-colored urine; light-colored bowel movements; difficulty breathing; stomach pain or swelling; nausea; vomiting; unusual muscle pain; loss of appetite for at least several days; lack of energy; extreme weakness or tiredness; feeling cold, especially in the arms or legs; dizziness or lightheadedness; or fast or irregular heartbeat.

Do not stop taking entecavir without talking to your doctor. When you stop taking entecavir, your hepatitis may get worse. This is most likely to happen during the first several months after you stop taking entecavir. Take entecavir exactly as directed. Be careful not to miss doses or run out of entecavir.If you experience any of the following symptoms after you stop taking entecavir, call your doctor immediately: extreme tiredness, weakness, nausea, vomiting, loss of appetite, yellowing of the skin or eyes, dark-colored urine, light-colored bowel movements, or muscle or joint pain.

If you have human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome (AIDS) that is not being treated with medications and you take entecavir, your HIV infection may become more difficult to treat. Tell your doctor if you have HIV or AIDS or if there is a chance that you have been exposed to HIV. Your doctor may test you for HIV infection before you begin treatment with entecavir and at any time during your treatment if there is a chance that you have been exposed to HIV. Entecavir will not treat HIV infection.

Keep all appointments with your doctor and the laboratory before, during, and for a few months after your treatment with entecavir. Your doctor will order certain tests to check your body’s response to entecavir during this time.

Ask your pharmacist or doctor for a copy of the manufacturer’s information for the patient.

Talk to your doctor about the risks of taking entecavir.

Adverse effects of oral antiviral therapy in chronic hepatitis B

World J Hepatol. 2017 Feb 18; 9(5): 227–241.

Bircan Kayaaslan, Rahmet Guner, Department of Infectious Disease and Clinical Microbiology, Yildirim Beyazit University Faculty of Medicine, Ataturk Education and Research Hospital, 06800 Ankara, Turkey

Author contributions: Both authors contributed equally to this paper with conception and design of the study, literature review and analysis, and drafting, critical revision, editing and approval of the final version.

Correspondence to: Bircan Kayaaslan, MD, Department of Infectious Disease and Clinical Microbiology, Yildirim Beyazit University Faculty of Medicine, Ataturk Education and Research Hospital, Bilkent Street no: 1, 06800 Ankara, Turkey. moc.liamg@nacibrd

Telephone: +90-505-8267777

Received 2016 Apr 28; Revised 2016 Nov 29; Accepted 2016 Dec 7.

Copyright ©The Author(s) 2017. Published by Baishideng Publishing Group Inc. All rights reserved.

This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial.

This article has been cited by other articles in PMC.

Abstract

Oral nucleoside/nucleotide analogues (NAs) are currently the backbone of chronic hepatitis B (CHB) infection treatment. They are generally well-tolerated by patients and safe to use. To date, a significant number of patients have been treated with NAs. Safety data has accumulated over the years. The aim of this article is to review and update the adverse effects of oral NAs. NAs can cause class adverse effects (i.e., myopathy, neuropathy, lactic acidosis) and dissimilar adverse effects. All NAs carry a “Black Box” warning because of the potential risk for mitochondrial dysfunction. However, these adverse effects are rarely reported. The majority of cases are associated with lamivudine and telbivudine. Adefovir can lead to dose- and time-dependent nephrotoxicity, even at low doses. Tenofovir has significant renal and bone toxicity in patients with human immunodeficiency virus (HIV) infection. However, bone and renal toxicity in patients with CHB are not as prominent as in HIV infection. Entecavir and lamivudine are not generally associated with renal adverse events. Entecavir has been claimed to increase the risk of lactic acidosis in decompensated liver disease and high Model for End-Stage Liver Disease scores. However, current studies reported that entecavir could be safely used in decompensated cirrhosis. An increase in fetal adverse events has not been reported with lamivudine, telbivudine and tenofovir use in pregnant women, while there is no adequate data regarding entecavir and adefovir. Further long-term experience is required to highlight the adverse effects of NAs, especially in special patient populations, including pregnant women, elderly and patients with renal impairment.

Keywords: Nucleoside/nucleotide analogues, Adverse events, Lamivudine, Chronic hepatitis B, Side effects, Safety, Telbivudine, Hepatitis B infection, Adefovir, Entecavir, Adverse effects, Tenofovir, Hepatitis B virus

Core tip: Extrahepatic effects of nucleotide analogues (i.e., myopathy, nephropathy, bone disorders) are more commonly indicated in current reports. Some of these adverse events can be attributed to their effect of causing mitochondrial dysfunction. These adverse events are named as “class effects” and mostly associated with lamivudine and telbivudine treatment. Adefovir is a well-known nephrotoxic agent. Nephrotoxic and bone density loss effects of tenofovir in patients with chronic hepatitis B (CHB) are not as clear as in those with human immunodeficiency virus infection. Serum creatinine, phosphorus and creatine kinase levels should be monitored. Safety profile is a major issue that should not be ignored in the treatment of CHB.

INTRODUCTION

Chronic hepatitis B (CHB) infection is one of the major causes of chronic liver diseases and affects an estimated 350 to 400 million people worldwide[1]. Up to 15%-40% of patients with CHB are at risk of developing complications including cirrhosis, hepatic decompensation and hepatocellular carcinoma (HCC)[2]. Prevention of disease progression and disease-related complications is the main goal of treatment in CHB and achieved by suppression of hepatitis B virus (HBV) DNA replication[2]. Because CHB requires long-term treatment in the majority of patients, the safety profiles of drugs become important in addition to their antiviral activities. Two different groups of antiviral agents have been approved for the treatment of CHB: Conventional or pegylated interferons (IFN or Peg-IFN), and oral nucleoside/nucleotide analogues (NAs)[2-4]. IFN/Peg-IFNs have some disadvantages, including severe side effects, aggravation of decompensated cirrhosis and autoimmune diseases. NAs have become currently the backbone of CHB treatment because they have been well tolerated by patients for decades without severe side effects[5]. There are currently five NAs approved for the treatment of CHB and they are classified into two groups: Nucleoside analogues (lamivudine, telbivudine and entecavir) and nucleotide analogues (adefovir dipivoxil and tenofovir dipivoxil fumarate)[6]. To date, a significant number of patients have been treated with NAs. Therefore, experience with the efficacy, resistance and safety profile of NAs has increased over the years. The aim of this article is to provide a review of the adverse effects of oral NAs in light of the current data.

All five NAs have a favorable safety profile[7]. However, undesired extrahepatic adverse events may occur during the treatment of CHB infection. The most common extrahepatic adverse events are renal dysfunction, decreased bone mineral density and some neurological findings. Because hepatitis B infection itself may lead to extrahepatic organ involvement[5], determining the source of extrahepatic manifestations may be difficult sometimes during the treatment of CHB. Extrahepatic adverse events may result from mitochondrial toxic effect of NAs. These adverse effects are generally named as “class effects”[8].

CLASS EFFECTS OF NAs

NAs suppress viral replication by the inhibition of the HBV polymerase enzyme. As NAs structures were similar to natural nucleosides, some of these agents can also inhibit human mitochondrial polymerase-γ and cause mitochondrial toxicity[3,5,9]. Mitochondrial toxicity was first noticed during human immunodeficiency virus (HIV) treatment with antiretroviral therapy. Nucleos(t)ide reverse transcriptase inhibitors (NRTIs) are activated by phosphorylation in the cell, and then inhibit HIV reverse transcriptase. Additionally, these drugs also inhibit a human polymerase-γ enzyme, which is responsible for the production of mitochondrial DNA (mtDNA) content. mtDNA-encoded proteins are present in multiple copies in each mitochondrion and responsible for encoding enzyme subunits of the respiratory chain function. Respiratory chain function is required for numerous metabolic pathways, including oxidative synthesis of ATP and synthesis of DNA. The depletion of mtDNA-encoded proteins results in mitochondrial dysfunction that causes impaired oxidative phosphorylation. The other result of human mitochondrial polymerase-γ inhibition is increased reactive oxygen species that cause cellular damage (Figure )[5,8,10]. The close relation between NRTIs and mitochondrial toxicity have been described in many reports[5,8,11]. Because NAs lead to a minimal mitochondrial polymerase-γ inhibition, NAs-associated mitochondrial toxicity cases have been rarely reported. All NAs carry a warning of mitochondrial toxicity as part of their prescribing information[5,8]. The clinical manifestations of mitochondrial toxicity include hematologic disorders, peripheral neuropathy, skeletal and cardiac myopathy, pancreatitis, hepatic failure and lactic acidosis[8,11].

Effects of nucleos(t)ide analogues. A: NAs show antiviral effect by inhibition of hepatitis B virus (HBV) polymerase; B: NAs also inhibits human mitochondrial polymerase-γ enzyme. Thus, mitochondrial DNA (mtDNA) can not be synthesized. Oxidative phosphorylation is impaired. There are two consequences of this: Impaired energy production and increased reactive oxygen species that cause cellular damage. NAs: Nucleos(t)ide analogues.

The most remarkable examples of mitochondrial toxicity were reported with clevudine therapy. Clevudine is a thymidine-nucleoside analogue approved in South Korea and the Philippines for the treatment of CHB. Although no mitochondrial dysfunction findings had been detected in preclinical studies, multi-center international phase III studies were terminated due to the emergence of clevudine-associated myopathy cases. Clevudine had been shown to be peripherally phosphorylated by mitochondrial thymidine kinase and to accumulate in cells rich in mitochondria[5]. South Korea revoked its approval because of indirect adverse effects[12-14]. The emergence of an association between clevudine and myopathy served as a reminder that all NAs have a potential risk for mitochondrial toxicity. Among the NAs, lamivudine and telbivudine are the agents most frequently reported to be associated with myopathy and peripheral neuropathy (Table ). Long-peripheral neurons were more susceptible to mitochondrial toxic effect of NAs due to length-dependent effect[15]. Xu et al[16] performed muscle and nerve biopsy in the 6 cases of NAs-associated myopathy or neuropathy and revealed similar changes in all the muscle and nerve biopsy samples of the patients in light or electronic microscopy and showed the decrease of the mitochondrial DNA by the quantitative real-time PCR in the affected muscle. Although an association between telbivudine and mitochondrial toxicity was not detected in vitro studies[12], telbivudine-associated myopathy and creatine kinase (CK) elevations have been reported repeatedly in real-life patients after phase studies. Myopathy may be accompanied by neuropathy in some of patients given telbivudine or lamivudine for the treatment of CHB infection. In one study, 3 of 6 patients with lamivudine or telbivudine-associated myopathy had a complaint of numbness in the distal end of limbs, suggesting peripheral neuropathy. The presence of neuropathy was confirmed by the electrophysiological studies and nerve biopsies by the study team[16]. Neuropathy cases have been reported more commonly in patients who have been treated with a combination therapy of telbivudine and Peg-IFN alfa-2a. Combination therapy provided a rapid reduction in HBV DNA level compared to telbivudine or Peg-IFN alfa-2a monotherapy. However, the risk of peripheral neuropathy has been reported to increase up to 20% in combination with Peg-IFN[10,12,15,17].

Table 1

Characteristics of approved oral antiviral drugs for chronic hepatitis B treatment

Myopathy is characterized by CK elevation alongside muscle pain and weakness. CK elevations are among the well-described adverse effects of NAs, but they are not specific for myopathy and may be associated with strenuous exercise and many other illnesses. CK elevations may occur in patients treated with all approved NAs for CHB. However, the incidence of myopathy is very low during the treatment with adefovir, entecavir and tenofovir, and similar to comparative groups. The causal relationship has not been elucidated as of yet[3,18]. Myopathy cases can be seen in every age group (25-82 years). There is no difference between male and female patients in terms of myopathy incidence. The mean onset time of myopathy from the initiation of NAs was reported as 6.4 mo, but it can occur even if in the 5^th year of treatment. Myopathy cases had been mostly reported from the South Korea and China, but the association between myopathy and race remains unclear[19].

LAMIVUDINE

Lamivudine is the first oral NA approved by the United States Food and Drug Administration (FDA) for the treatment of CHB in 1998 at a dose of 100 mg/d. It is an analogue of cytidine [2′,3′-dideoxy-3′thiacytidine (3TC)] and phosphorylated to its active triphosphates form by intracellular deoxycytidine kinase enzyme. The active anabolite prevents HBV replication by competitively inhibiting viral reverse transcriptase and terminating proviral DNA chain extension[20]. Lamivudine has been the most experienced oral antiviral in CHB patients[8,20]. It can be used effectively in a broad range of patients, with minimal adverse effects[21]. However, long-term treatment of lamivudine is associated with high rates of drug resistance, which lead to virological relapse and biochemical flare[1-3,8]. Therefore, lamivudine is recommended as a second-line therapy for the treatment of CHB[1,2].

Long-term lamivudine treatment was generally well-tolerated by CHB patients[21,22]. In the GLOBE trial, a large, multi-center phase III study, of the 1367 CHB patients who received telbivudine and lamivudine, adverse events were reported in 23% of the lamivudine recipients, similar to the findings for the telbivudine recipients (29%). The most common adverse events were upper respiratory tract infection (16.2%), nasopharyngitis (13.1%), headache (13.4%) and fatigue (12.1%). Of the patients, 6% (44) experienced serious adverse events[23]. The primary adverse event was reported as hepatic flares due to emergence of lamivudine-resistant HBV with prolonged treatment. After 4 years, hepatic decompensation and other severe adverse effects increased among patients with lamivudine resistance[24]. In an Asian study by Leung et al[22], 12% (n = 7) of patients treated with lamivudine experienced severe side effects. Most of these were increased transaminase and CK levels, and resolved spontaneously. Increased alanine aminotransferase (ALT) levels were generally associated with emergence of YMDD mutant strains and had no clinical importance. In another study conducted among 998 patients with hepatitis B e antigen (HBeAg)-positive compensated liver disease who were treated with lamivudine for up to 6 years, lamivudine demonstrated a good safety profile, with only a 5% rate of severe adverse events[24]. Similarly, lamivudine has been found to be effective in HBV DNA decrease, ALT normalization and histological improvement, and it was well-tolerated by patients with cirrhosis. Lamivudine had been used in patients with acute or fulminant hepatitis without any adverse event, and led to fast recovery and increased survival[25].

Lamivudine has a good safety profile in different patient populations having some comorbid diseases. It is the most experienced drug for preemptive treatment of hepatitis B infection in solid-organ recipient and immunosuppressive patients[1]. There are limited data for experiences with the other NAs[26]. Although highly potent oral NAs with high genetic barriers to antiviral resistance, such as entecavir and tenofovir, have become the current preferred regimen, lamivudine remains a therapeutic option for hepatitis B prophylaxis since it is the most cost-effective choice for these patients[27,28]. Lamivudine has been well tolerated by patients receiving immunosuppressive treatment. In a systematic review investigating the preventive effect of lamivudine on chemotherapy – induced hepatitis B-related morbidity and mortality in hepatitis B surface antigen (HBsAg)-positive patients with cancer, none of the eight studies that recorded safety profile of lamivudine reported any significant adverse events[29]. Lamivudine has also been used safely in children without any serious side effects. In one study, only slight and transient increase of ALT levels were reported in 6.8% of children with CHB, without any complaint or clinical findings[30].

Serious adverse events have rarely been reported with lamivudine treatment[31,32]. Lamivudine-induced rhabdomyolysis is one of them and characterized by a triad of muscle weakness, myalgia and abnormal laboratory findings including CK elevation, increased urine and blood myoglobin level, and acute renal injury. Tubular damage and obstruction is considered the main reason underlying pathogenesis[31-33]. Clinical and laboratory findings improve generally within a few days after cessation of the drug. However, in one case, rhabdomyolysis relapsed after readministration of lamivudine for HBV infection prophylaxis and resolved completely after discontinuation of the drug again[34]. The mortality rate was reported to be high in patients who developed rhabdomyolysis and may be reduced by the early recognition of the disease and fluid resuscitations[31]. Lamivudine-induced acute dystonic reaction was reported in 2 patients, and the acute dystonia resolved after discontinuing the lamivudine therapy[35]. Lamivudine-associated ichthyosiform eruptions and pancreatitis cases have been reported in the literature[25,36-38].

TELBIVUDINE

Telbivudine is a thymidine nucleoside analogue which selectively inhibits HBV DNA synthesis. It was approved in 2006 for the treatment of CHB patients at a dose of 600 mg/d. Telbivudine is a more potent NA against HBV compared to lamivudine and adefovir[3,39]. However, high resistance rates limit the use of telbivudine as the firstline therapy[2,3]. Upper respiratory tract infection, nasopharyngitis, fatigue and headache were reported as the most frequent adverse events associated with telbivudine use. Adverse events’ frequencies were found to be similar in lamivudine and telbivudine groups. However, Grade 3/4 increase in CK level occurred more commonly in patients given telbivudine (12.9% vs 4.1%), but these were not associated with musculoskeletal adverse events and no rhabdomyolysis cases were detected during the study period[23]. CK elevations were generally self-limiting and asymptomatic. Discontinuation of telbivudine was not required in most of the cases. Telbivudine-associated myopathy and CK elevations have been reported in several studies[12,40-42]. Zou et al[41] conducted a prospective study to investigate clinical features and risk factors of telbivudine-associated myopathy and CK elevations. The serum CK levels of 200 patients treated with telbivudine were analyzed. The 3-year cumulative incidence of CK elevations was considerably high (84.3%). Nine patients (5%) experienced myopathy and were required to discontinue telbivudine therapy in 3 of those. None of the patients developed rhabdomyolysis. CK elevations were reported to occur in males more often than in females and in those with HBeAg negativit and aged < 45 years. In another study in which 105 patients given telbivudine were evaluated for adverse reactions, 5 presented serious adverse events. There was nervous system damage in 3 of the cases and cardiac arrhythmia in 1 case. All 5 patients had elevated CK enzymes. Therefore, it is recommended that CHB patients treated with telbivudine should be monitored closely for musculoskeletal symptoms and CK enzyme levels[3].

Some infrequent but serious side effects were reported in previous studies. Lactic acidosis is one of them and it was reported also in patients treated with all the other nucleos(t)ide analogues[43]. It results from mitochondrial dysfunction or loss due to the inhibitor activity of telbivudine on human mitochondrial DNA polymerase-γ. A few lactic acidosis cases depending on telbivudine therapy were reported in the literature. The symptoms of patients were anorexia, nausea, vomiting, muscle pain and weakness in upper and lower extremities. The laboratory tests revealed elevated serum CK levels and hyperlactatemia[43]. One patient’s complaints continued even after the withdrawal of telbivudine treatment, and the patient recovered after venovenous hemodiafiltration. To diagnose hyperlactatemia, the patients should be monitored by periodic (3-6 mo interval) lactate measurements, in addition to the CK monitoring.

The mechanism of adverse events associated with telbivudine use has not yet been defined. Because adverse events may occur in multiple organs including muscles, nervous and cardiac systems, Zhang et al[42] suggested that the mechanism is associated with cell energy metabolism. Deficiency in manufacture of the energy molecule ATP and, therefore, inadequate supplementation of substrate for oxidative phosphorylation causes mitochondrial damage. Highly energy-dependent organs such as nerves, heart and muscles are the most susceptible to mitochondrial dysfunction. Telbivudine leads to adverse events in these organs. However, to establish a link between adverse events and mitochondrial disease, muscle biopsy and DNA studies should be done[42].

Synergistic effect can occur in case of simultaneous use of two drugs. A study comparing telbivudine and lamivudine combination and lamivudine monotherapy reported that the addition of telbivudine to lamivudine treatment did not increase the toxic adverse effects[44]. However, the combination of telbivudine with Peg-IFN caused peripheral neuropathy in 17.0% of patients. For this reason, telbivudine should not be recommended in combination with Peg-IFN[8].

ADEFOVIR DIPIVOXIL

Adefovir dipivoxil is an oral prodrug of the nucleotide analogue adefovir, approved for CHB treatment at 10 mg/d dose in 2002. It was used initially in patients with HIV infection, but its use was abandoned due to the fact that higher doses of adefovir led to nephrotoxicity[8]. Adefovir improves histological, biochemical and virological outcomes in CHB patients with lamivudine resistance. The rates of adverse events in patients given adefovir are similar to those given placebo[45-48]. The most common adverse events were pharyngitis, asteni, headache, abdominal pain, flu-like symptoms and nausea[45]. In a randomized controlled study, adverse events were similar in two groups, but headache and abdominal pain occurred more frequently in the adefovir group than in the placebo group. However, these adverse events did not lead to discontinuation of the study drug[48]. Adefovir is associated with dose-dependent renal toxicity. The nephrotoxic effect of adefovir was discussed in the section below on “Renal Safety of NAs”.

Myopathy cases were reported in CHB patients given adefovir treatment, but its incidence was similar to patients receiving placebo[12]. Adefovir-related lactic acidosis may occur when combined with other NAs[49]. The development of resistance to adefovir therapy is another undesirable event. Drug resistance was reported in 26% of CHB patients treated with adefovir, after 5 years[8]. The resistance rate of adefovir in patients with lamivudine resistance who were given adefovir add-on lamivudine rescue therapy was 6% at the end of 5 years[50]. To optimize therapy in lamivudine-resistant patients, it is recommended not to discontinue lamivudine therapy for a while after initiating adefovir[8].

ENTECAVIR

Entecavir is a highly selective guanosine nucleoside analogue, approved by the FDA at a dose 0.5 mg in treatment naive and 1 mg/d in lamivudine-resistant CHB patients in 2005[3,51]. It inhibits three steps of viral replication, which involves HBV polymerase priming, reverse transcription of the pre-genomic messenger RNA and synthesis of the positive-stranded HBV DNA[3]. Entecavir is a well-tolerated antiviral agent in CHB patients, with rates of adverse events similar to placebo or lamivudine therapy. In a comparative study, the adverse event rate was found to be similar in patients given entecavir monotherapy to those given combination of entecavir and IFN[52]. Long-term use was reported to be associated with a very low rate of side effects. Adverse events were not dose-related; their frequencies were similar between 0.5 or 1 mg doses of entecavir[51,53]. The most frequent adverse events in clinical trials were headache (17%-23%), upper respiratory tract infection (18%-20%), cough (12%-15%), nasopharyngitis (9%-5%), fatigue (10%-13%), dizziness (9%), upper abdominal pain (9%) and nausea (6%-8%). Most of these adverse effects were mild or moderate severity and did not require discontinuation of the drug[51,54]. Severe adverse events accounted for 7%-10% and discontinuation of therapy accounted for 1%-2% of patients[51]. In a randomized controlled study, severe adverse events occurred in 4.7% of pediatric patients (n = 8), and only one of them discontinued entecavir due to headache. This adverse event was not attributed to the study drug[54]. Although preclinical data reported an association between long-term entecavir use and carcinogenicity, to date, no evidence has been detected regarding occurrence of cancer due to entecavir therapy[55].

The FDA requires all approved NAs to include a “Black Box” warning in their product label regarding potential mitochondrial toxicity[56]. Entecavir is the most innocent antiviral agent leading to mitochondrial toxicity among the effective therapies in CHB treatments. In long-term cell culture studies, entecavir has been observed to have very low potential for mitochondrial toxicity in in vitro cultures studies at the highest levels tested, 300 μmol/L. Combination of entecavir with the other NAs also did not cause an increase in the risk of other drugs[8,57]. Entecavir-associated myopathy and peripheral neuropathy cases were very rarely reported in the literature[3,15,19]. Although a study reported similar CK elevation rates with both telbivudine and entecavir therapy, there were not many studies supporting this[58]. In a meta-analysis, six randomized controlled trials involving 555 patients treated with telbivudine and entecavir for 24 or 52 wk were evaluated. Both drugs had similar antiviral and biochemical effects. However, the entecavir group was reported have greater safety than the telbivudine group, in terms of adverse events[59]. In another meta-analysis comparing the effects of telbivudine and entecavir in HBeAg-positive CHB patients, thirteen trials (3925 patients in total) were evaluated. Adverse effects were reported in 10 trials and CK elevations in 5 trials. The rates of increased CK were found to be statistically higher in the telbivudine group than in the entecavir group[60].

Lactic acidosis can also occur during treatment with NAs as a result of mitochondrial toxicity. US prescribing information for entecavir and the other NAs carries a warning regarding the risk of lactic acidosis in CHB patients treated with NAs[61-64]. Entecavir is a good option for the treatment of CHB patients with decompensated cirrhosis because of the rapid effect on HBV decline and low resistance rates. However, it was suggested that a high Model for End-Stage Liver Disease (MELD) score that is used to detect highly impaired liver function can be associated with lactic acidosis in patients receiving entecavir[49]. One retrospective study identified 5 cases of lactic acidosis among 16 entecavir-recipient CHB patients with cirrhosis. One of them died, and the lactic acidosis resolved within 4-5 d after withdrawal of entecavir in the remaining 4 cases. All patients who developed lactic acidosis had a MELD score of at least 20 (22-38), whereas the patients who did not develop lactic acidosis had a MELD score below 18. A significant (P = 0.002) correlation was seen between the MELD score and the development of lactic acidosis[49]. However, a small retrospective study did not find an increased risk of lactic acidosis in the CHB patients with decompensated liver disease and high MELD scores during entecavir treatment, compared to those who have non-HBV-related decompensated liver disease and similar clinical features[65,66]. Entecavir has been reported to have a high safety profile in decompensated patients and recommended as one of the first-line treatment choices of CHB patients with decompensated liver disease in an Asian-Pacific consensus statement[67,68]. Nevertheless, the patients should be monitored cautiously for the risk of lactic acidosis during the treatment and entecavir should be suspended in the case of suspected lactic acidosis[49,66].

Patients with severe acidosis complained of nausea, dyspnea and weakness, and showed a reduced general physical condition, impaired consciousness and tachypnea. In addition, 2 of 3 patients with severe acidosis suffered from paresthesia and the remaining 1 patient developed hepatic steatosis typical for mitochondrial toxicity. ALT flares, potentially leading to decompensated hepatic disease, can be another serious health problem in a patient given entecavir for CHB. In clinical trials, ALT flare had been reported to occur in a small percentage of patients treated with entecavir and to resolve even if the treatment continued. In an open-label study evaluating the safety and tolerability of entecavir, Grade 3 and 4 adverse events were detected in 19% of the patients, with only 4% of them possibly related to entecavir. These Grade 3 and 4 adverse events were myalgia, neuropathy, increased lipase, increased creatinine and lactate, CK elevation, decreased bicarbonate and pancreatitis. Entecavir treatment was discontinued in only 1% of cases due to adverse events. ALT flares were reported in 3% of the patients during the treatment, and were associated with inhibition of viral replication, at least 2 log₁₀ decrease of HBV DNA[68]. In a multi-center European study investigating the incidence and outcome of ALT flares during long-term entecavir in CHB, 729 patients treated with entecavir for a median of 3.5 years were evaluated. Flares were classified as host-induced (preceded by HBV DNA decline), virus-induced (HBV DNA increase) or indeterminate (stable HBV DNA). A total cumulative incidence of ALT flare was 6.3% (30) at year 5. Of them, 12 were host -induced and associated with biochemical remission. HBeAg and HBsAg seroconversion was observed in only these host-induced flares. Virus-induced flares were reported to be associated with entecavir resistance and non-compliance to the therapy[69]. Therefore, long-term use of entecavir is generally safe and associated with low rates of serious adverse events, and discontinuation of the treatment is rarely required. ALT flares were low in patients receiving entecavir and generally associated with the improvement of liver disease. In current guidelines, entecavir is also recommended as treatment and prophylaxis of CHB infection in patients with renal transplant due to being an agent without signs of nephrotoxicity[2].

TENOFOVIR

Tenofovir disoproxil fumarate (TDF) is a prodrug of tenofovir that has been approved as a nucleotide analogue by the United States FDA for use in HIV infection in 2001 and in CHB infection in 2008 at a dose of 300 mg[8]. TDF is converted to tenofovir by hydrolysis and then phosphorylated by cellular enzymes to tenofovir diphosphate. It inhibits (potentially) HBV DNA polymerase and reverse transcriptase. Tenofovir, one of the main components in antiretroviral regimens, plays a key role in HIV treatment. It is also a highly potent inhibitor of HBV DNA replication and recommended as a first-line treatment choice in CHB by the current clinical guidelines due to the absence of resistance to the drug[1,70]. The molecular structure and general safety profile of tenofovir is similar to adefovir, but nephrotoxicity has not been a major problem with tenofovir at therapeutic doses. Therefore, it can be used at higher doses compared to adefovir and leads to more effective responses in HBV DNA decline. The nephrotoxic effect of tenofovir is discussed in detail in the below section on “Renal Safety of NAs”.

In phase III studies of tenofovir, the adverse event profiles were similar to those in the comparative arm of adefovir. The most frequent adverse events were headache, nasopharyngitis, back pain and nausea. Treatment-related adverse events were detected in 6% of patients, serious adverse events in 4% and adverse events that required discontinuation of tenofovir in less than 1%[8,55]. A 3-year, prospective real-world study (Vireal group) reported 68 adverse events in 41 (9.3%) patients among a total of 440 patients receiving tenofovir. Adverse events occurring in more than one patient were renal disorders (n = 11), abdominal pain (n = 8), asthenia (n = 7), nausea (n = 6), vomiting (n = 5) and diarrhea (n = 5). Nine of the 16 serious side effects were reported to be tenofovir-related (visual impairment, nausea, asthenia gait disturbance, weight loss, depression, muscular weakness, muscular pain and psoriasis)[71].

Osteomalacia can occur during long-term tenofovir treatment. In randomized clinical trials, a great loss of bone mineral density (BMD) had been well-described in patients with HIV infection treated with tenofovir[55,72-74]. However, tenofovir-related bone fractures were not reported in patients with HBV monoinfection[55]. During the 3-year prospective follow-up, fractures were observed in 1% of 375 HBeAg-negative and 266 HBeAg-positive patients, but none were related to tenofovir[75]. The primary responsible mechanism for bone density loss is believed to be related with inhibitory effects of HIV proteins or immune status in osteoblasts and an increased osteoclastic activity. Modifying effects of tenofovir on osteoblast gene expression and function was the other mechanism defined in recent reports[72]. The exact mechanism of bone toxicity in CHB is not clear. Possibly, proximal tubular damage caused by TDF therapy leads to hypophosphatemia and, indirectly, to inadequate mineralization of bone matrix[3]. There have been case reports regarding tenofovir-associated osteomalacia. A recent study including 170 patients with CHB infection compared patients treated with tenofovir (n = 122) and control patients (n = 48) in terms of bone health[72]. The prevalence of BMD loss in patients receiving tenofovir was similar to those who were not exposed to tenofovir. Tenofovir was reported to be associated with a lower T score only in the hips. Additionally, in the study, there was no significant correlation between duration of exposure to tenofovir and reduction in BMD at any side. The risk factors for reduction in BMD other than tenofovir exposure were the known classical factors including advancing age, lower body mass index and smoking[72-74]. A large retrospective study including 53500 subjects in Hong Kong (46454 untreated and 7046 treated) investigated renal and bone events in CHB patients with and without NAs. The patients treated with NAs had similar risk of hip fracture, spine fracture and all fracture, compared to untreated CHB patients. Treatment with nucleotide analogues, compared to nucleoside analogues, was found to increase only the risk of hip fracture but not the other side fracture, and the overall fracture rate was low[76]. Additionally, BMD reduction was demonstrated to remain constant on a plateau from year 4 through year 7 of tenofovir treatment, for both hip and lumbar spine[77]. Thus, we may conclude that BMD reduction is not a progressive event and is detected in the first years of treatment[78]. These are important findings due to CHB infection requiring lifelong treatment in the majority of patients because the discontinuation of NAs after sustained viral response have a high risk of relapse. Tenofovir can be preferred and used safely in CHB patients in the long-term. Nevertheless, BMD should be periodically performed in patients with CHB infection treated with tenofovir[79]. Osteoporotic patients, especially with advanced age and smoking history, should be monitored more closely and, if required, consulted with a physical rehabilitation specialist.

RENAL SAFETY OF NAs

The adverse effect of NAs on renal function is an important issue that should be carefully evaluated, since HBV infection alone carries an increased risk of renal impairment[80]. All NAs are excreted through kidneys in unchanged forms and some of them are associated with dose-dependent nephrotoxicity[3]. Nephrotoxicity results from proximal tubular damage and presents with elevated serum creatinine, proteinuria, nephrogenic diabetes insipidus, hypophosphatemia or the more severe form, Fanconi syndrome[15]. Mauss et al[81] reported a milder decrease in renal function with CHB therapy irrespective of medications. Comorbidities such as diabetes, hypertension and underlying chronic renal disease may also contribute to the nephrotoxic effect of NAs and aggravate renal dysfunction. In a study analyzing effects of NAs and comorbidities on renal function in 4178 CHB patients, age, diabetes, chronic renal disease, renal transplantation and simultaneous administration of diuretics were found to be independent risk factors for the rapid progression of renal disease[81].

Renal toxicity is the most noticeable side effect of adefovir. It is generally dose- and time-dependent, and reversible with dose-adjustment or discontinuation of the drug[15,45,82-84]. In the majority of studies, nephrotoxicity was defined as an increase ≥ 0.5 mg/dL from baseline in serum creatinine or a serum phosphorus value of < 1.5 mg/dL on two consecutive occasions[83]. In previous studies, including randomized controlled ones, adefovir at 30 mg/d was reported to be nephrotoxic, but adefovir at 10 mg/d was well tolerated and did not lead to an increase in renal dysfunction compared to placebo[45,85]. In a study including a total of 515 patients with CHB, three groups who were treated placebo (n = 170), adefovir dipivoxil at 10 mg (n = 172) or adefovir dipivoxil at 30 mg (n = 173) were compared in terms of response to the treatment and adverse events rates[45]. The safety profile was similar in two groups, the placebo group and the adefovir dipivoxil at 10 mg per day group. There was no significant change in median serum creatinine level at wk 48 of the treatment in these groups. However, 8% of the 30-mg group experienced an increase from baseline of 0.5 mg/dL (44 μmol/L) or greater in the serum creatinine level. The prolonged use of adefovir carries an extra risk of renal dysfunction. The incidences of increased creatinine level and hypophosphatemia were reported to be increased with longer usage of adefovir, even in patients receiving standard low-dose drug.

In recent years, Fanconi syndrome cases due to long-term use of adefovir have been increasingly reported, especially in East Asian populations[83]. Fanconi syndrome is defined as hypophosphatemia and a slight increase in serum creatinine, resulting in proximal renal tubular dysfunction. Additionally, osteomalacia may develop secondary to hypophosphatemia. The patient’s main symptoms can be muscular weakness and bone pain involving the knees, ankles and ribs. Clinicians should be aware of this potential complication and monitor periodically the renal function and serum phosphate level in any patient receiving adefovir[83,86]. In a current meta-analysis, including seven randomized controlled trials, four cohort studies and six single-arm studies, adefovir treatment was not found to be associated with increased nephrotoxicity in the randomized controlled trials. However, the cohort studies showed an increased nephrotoxicity risk in patients given adefovir, and the single-arm studies revealed an approximately 1.7-fold increased risk of renal dysfunction in patients given adefovir compared to those treated with all other NAs[82]. The authors drew attention to the differences between the risk of nephrotoxicity in randomized controlled trials and cohort studies and emphasized that since the randomized controlled trials were small-sized and short observational studies, the safety data may be inadequate and that these studies may have underestimated the adverse events. Current evidence indicated an increased risk of nephrotoxicity in CHB patients treated with adefovir.

The mechanism of adefovir nephrotoxicity was poorly understood. Nephrotoxicity may result from the apoptotic or mitochondrial toxic effect of adefovir in the renal tubular epithelium. The deterioration of the balance between the active adefovir uptake from blood into proximal tubular cells, the secretion into urine, and accumulation in proximal tubular cells represent the primary mechanism of tubular toxicity.

Fanconi syndrome is a rare but serious adverse effect of adefovir treatment. Fanconi syndrome is characterized by proximal renal tubular toxicity and leads to increased urinary excretion of amino acids, uric acid, bicarbonate, glucose and phosphate, and impaired re-absorption of these solutes. Clinical manifestations in adults include polyuria, polydipsia, dehydration and osteomalacia[87]. There are a significant number of cases of adefovir-associated Fanconi syndrome in the literature. Most cases occurred after prolonged use of the drug and resolved after cessation of adefovir or switching to another NA. The lowest dose of adefovir (10 mg) can also lead to Fanconi syndrome[88]. Normalization of creatinine level may require more than 1 year. In a retrospective case series study including 35 patients with Fanconi syndrome, hypophosphatemia, increased urinary phosphate excretion and elevated alkaline phosphatase were detected in all patients. Although serum phosphate levels rapidly increased, especially within the 4 wk after adefovir discontinuation, serum creatinine levels did not decrease to normal range even 1 year after discontinuation of therapy[88]. Fanconi syndrome was rare in CHB patients treated with tenofovir; it has been reported especially in cases of HIV-HBV coinfection[87,89-91].

Despite tenofovir being a higher dose preparation (300 mg/d) that has similar molecular structure with adefovir, renal toxicity has been less commonly detected[3]. In animal studies, tenofovir was reported to be associated with renal dysfunction[3,84]. The mechanism of nephrotoxicity is poorly understood, but it may involve proximal tubular damage, mitochondrial toxicity and apoptosis[8,92].

Tenofovir has been shown to have a potential nephrotoxic effect in patients with HIV infection who were treated for an especially extended period. However, in clinical trials, nephrotoxicity does not seem to be a major problem in HBV monoinfection[3,55,93]. Increases in serum creatinine of > 0.5 mg/dL were reported to be detected in 1% of patients and remained stable over 4 years in less than 1% of patients, with increased serum creatinine levels of 0.5 mg/dL[93]. Nevertheless, renal functions and serum phosphate should be monitored regularly in patients treated with tenofovir[3].

In a study conducted by the Vireal group, a slight decrease of mean glomerular filtration rate (GFR) was reported during tenofovir therapy. Median change in creatinine clearance and serum creatinine level remained stable over time. Of the patients, 15% (n = 65) had a decline in GFR of ≥ 20% and 6% (n = 26) had a decline in GFR of ≥ 30% compared to baseline. Tenofovir treatment was discontinued in 23 patients due to adverse events. Seven of them were associated with renal disorders (n = 3, renal failures; n = 2, renal impairments; n = 2, renal tubular disorders)[71]. Patients who have an underlying renal impairment or HIV coinfection and those who receive a nephrotoxic drug are at increased risk of nephrotoxicity. In a study comparing tenofovir and entecavir in the same number of patients, diabetes and transplantation but not tenofovir treatment were found to be associated with increased risk of renal impairment[94]. A significant number of studies reported that tenofovir did not lead to clinically relevant changes in renal function[79,95].

In a prospective open-label study, conducted by Heathcote et al[75], creatinine and creatinine clearance were reported to remain stable during a 3-year period, with a change in creatinine of 0.02 mg/dL at week 144. Two patients experienced a 0.5 mg/dL increase in creatinine and 4 patients a reduction in serum phosphorus < 2 mg/dL. All patients remained in the study and continued the tenofovir therapy. The long-term follow-up results of tenofovir therapy support the previous data. At year 6, less than 1.5% experienced impairment in renal function (≥ 0.5 mg/dL increase in serum creatinine from baseline, phosphorus < 2 mg/dL, or CrCL < 50 mL/min) with tenofovir treatment[55]. Recently, Buti et al[77] reported 7^th year results of tenofovir treatment for CHB. Of 585 patients, 21 (3.6%) experienced renal function impairment. A serum creatinine increase ≥ 0.5 mg/dL above baseline were confirmed in only 10 patients (1.7%). The patients who did and did not develop renal insufficiency were statistically different in terms of mean age (47 years vs 40 years; P = 0.003), baseline mean creatinine clearance (98.5 mL/min vs 117.4 mL/min; P = 0.003) and main serum phosphate (2.8 mg/dL vs 3.3 mg/dL; P = 0.002). Despite the absence of significant evidence that tenofovir is a nephrotoxic agent, possible proximal tubular damage should still be kept in mind[3]. The patients with normal renal function or mild renal impairment who have no increased risk for renal toxicity should be monitored every 6 mo for serum creatinine and phosphorus. The patients with impaired renal function or underlying comorbidities that show increased renal failure may be monitored more frequently[96]. Dose-adjustment should be made according to the renal impairment[3].

Tenofovir safety was also similar in elderly and younger patients[59]. There is little experience with tenofovir treatment in renal transplantation. One study reported 7 HBV-positive organ transplant recipients (n = 3, kidney; n = 1, liver; n = 3, hearts) who were safely and effectively treated with tenofovir. No adverse events or kidney rejection were observed. There were no statistically significant changes in renal functions[97].

In contrast to the nucleotide analogues, nucleoside analogues are not generally associated with renal adverse events. Increase in serum creatinine was reported in less than 1% of patients treated with entecavir[49]. In the study of Tsai et al[98], entecavir and telbivudine were found to be associated with GFR improvement. Despite the absence of strong evidence, the current guidelines recommend entecavir as the best option in renal transplant recipients due to lack of data demonstrating a major renal toxicity with entecavir[2,99-101].

Interestingly, telbivudine improves renal functions[3,8,81]. Several real-life studies have shown that treatment with telbivudine increases GFR in CHB patients. The GLOBE study and long-term extension studies had revealed that long-term telbivudine treatment was associated with a sustained improvement in renal function in patients with compensated and decompensated cirrhosis who had an increased risk of renal impairment[23,102]. Gane et al[102] indicated an improvement in renal function with telbivudine treatment by the calculation of GFR using the Modification of Diet in Renal Disease, Chronic Kidney Disease Epidemiology Collaboration, and Cockcroft-Gault methods. The increment of GFR was also shown in patients at increased risk for renal impairment: +17.2% in patients with baseline GFR of 60-89 mL/min per 1.73 m², +11.4% in patients older than 50 years and +7.2% in cirrhotic patients. Additionally, improved renal function has been reported to be maintained for 4-6 years. In a study investigating the renoprotective effect of telbivudine on patients receiving adefovir-based combination therapy, combination of adefovir and telbivudine was found to have a more protective effect on renal functions than the combination of adefovir and entecavir, combination of adefovir and lamivudine, adefovir alone or entecavir alone[79]. Preemptive telbivudine use was reported to prevent renal deterioration caused by cisplatin-based chemotherapy in patients with advanced HCC[103]. Additionally, telbivudine is recommended in the prophylactic treatment of CHB in patients with renal transplant due to its renoprotective effect on transplanted patients[2]. Telbivudine is a good option, especially in patients with renal impairment or in those with risk factors for renal disease.

All NAs are cleared by kidneys and their dosage should be adjusted in patients with creatinine clearance below 50 mL/min[104]. To minimize the risk of nephrotoxicity, simultaneous administration of the other nephrotoxic drugs should be avoided. Secondly, all patients with CHB infection who are treated with adefovir or tenofovir should be regularly monitored for serum creatinine and phosphate levels and drug dose should be modified if creatinine increases by more than 0.5 mg/dL above baseline or phosphate level decreases below 2.0 mg/dL, to the needed dose[8].

SAFETY IN PREGNANCY

Mother-to-child-transmission remains the main route of hepatitis B acquisition, especially in endemic countries[105]. Despite postnatal use of immune globulin and vaccine, mother-to-child transmission of HBV infection still occurs. Intrauterine transmission is considered the main reason underlying immunoprophlaxis failures[2,106]. High HBV DNA levels and HBeAg-positive status are the most important risk factors for perinatal HBV transmission. Thus, reducing maternal HBV DNA level has become the main preventive measure of perinatal mother-to-child transmission[106]. Current guidelines recommend initiating NAs in pregnant females with high HBV DNA levels (above > 10^6-7 IU/mL) at 28-32 wk of gestation and cessation of NAs after delivery or 4-12 wk after delivery in females who do not have a risk for ALT flares and pre-existing advanced liver fibrosis/cirrhosis[2,105].

Two of five NAs approved for the treatment of CHB, telbivudine and tenofovir, are classified as category B in the United States FDA Pregnancy Categories (meaning that no risk was observed in animal studies; however, there are no adequate and well-controlled studies performed in pregnant women). The other three NAs, lamivudine, entecavir and adefovir, are classified as category C (meaning that an adverse effect on the fetus have been shown in animal studies, but there are no adequate studies in humans)[107] (Table ). Prospective studies have revealed that fetal abnormality rates in mothers treated with NAs is low, and similar to those in the general population[3]. Lamivudine is the most experienced NA in pregnancy and it has been used safely in preventing mother-to-child transmission of HIV infection for 2 decades[2]. In randomized controlled studies, lamivudine has been shown to be effective in preventing mother-to-child-transmission when used in the third trimester of pregnancy and early postnatal period. There was no significant difference in the incidence of fetal adverse effects between lamivudine and placebo groups[108,109]. The Antiretroviral Pregnancy Registry (APR) provides updated fetal safety data on various drugs used in pregnancy, and includes data from January 1989 to date. Up to 31 July 2015, APR reported newborn defect rates as 3.1% during the first trimester of 4566 pregnant women and 2.9% during the second/third trimester of 7263 pregnant women who were exposed to lamivudine. These rates were not different from those reported in the general population[110]. However, lamivudine administration, even if for short-term use such as during pregnancy, has a risk of selecting resistant strains due to poor antiviral activity[106]. Current guidelines do not recommend lamivudine as first-line therapy for the treatment of CHB infection in pregnant women[1,2].

Tenofovir is recommended in current guidelines for preventing mother-to-child transmission in pregnant women with high viremia based on its potent antiviral activity, high barrier to resistance and being safe[1,2]. Data on tenofovir safety has been usually obtained from patients with HIV infection. It has been safely used in pregnant women with HIV infection for a relatively long time. APR reported newborn defect rates as 2.3% during the first trimester of 2608 pregnant women and 2.1% during the second/third trimester of 1258 pregnant women, which is similar to the rates in the general population. In a retrospective study, conducted in 45 HBeAg-positive pregnant women with high HBV DNA levels, tenofovir was found to be effective in preventing vertical transmission and no significant fetal adverse events were observed[111]. The other multi-center prospective observational study reported tenofovir to be more effective than lamivudine in preventing vertical transmission[112]. These data are supported by other studies[113].

Telbivudine has greater potency than lamivudine in decreasing HBV DNA level and it is recommended by current guidelines in the prevention of mother-to-child transmission of HBV infection. Use of telbivudine during the second/third trimester of pregnancy was reported to be effective and safe. Compared to placebo, no serious adverse events were found in telbivudine-treated mothers and their infants[3,12]. Despite the relatively low resistance rate compared to lamivudine, telbivudine resistance may occur during therapy[105]. There are no adequate and well-controlled studies on the safety profile of entecavir and adefovir in pregnant women infected with CHB[15].

Breast-feeding is discouraged during maternal NAs treatment due to the uncertain safety on infants[1,2]. Lamivudine is concentrated in breast milk. However, its amount in infants exposed to lamivudine during breast-feeding is accepted to be insignificant (approximately 2% of the recommended daily treatment dose)[114]. Similarly, tenofovir concentrations in breast milk have been reported, but infants are exposed to a small amount because its oral bioavailability is limited[1]. There is no adequate evidence to recommend the use of entecavir and adefovir during the breast-feeding period[110,111]. Lamivudine or tenofovir is regarded as the choice in breastfeeding mothers who needed to receive treatment for HBV infection.

CONCLUSION

In light of the current data, the treatment of CHB seems to be a life-long therapy. Thus, the long-term safety of the drugs is one of the main factors that influence treatment decision. To date, five oral NAs have been approved for the treatment of CHB. All NAs are generally safe and well-tolerated by CHB patients. All NAs carry a “Black Box” warning about mitochondrial dysfunction. The majority of mitochondrial toxicity cases are associated with lamivudine and telbivudine and generally present as myopathy, neuropathy or lactic acidosis. No increased incidence of myopathy was reported with adefovir, tenofovir and entecavir treatment, compared to placebo. Adefovir is a well-known nephrotoxic agent and may cause renal proximal tubular dysfunction. Fanconi syndrome cases have been increasingly reported in long-term adefovir therapy. Tenofovir has potential nephrotoxic and bone density loss effects, especially in patients with HIV coinfection. Entecavir and lamivudine are not generally associated with renal adverse events. Interestingly, telbivudine has the effect of improving renal function. Serum creatinine, phosphorus and CK levels should be monitored, especially in patients treated with adefovir and tenofovir. Since BMD reduction may occur during tenofovir treatment, BMD measurements should be periodically performed. Although entecavir is suggested to be associated with lactic acidosis in CHB patients with high MELD scores, its use in compensated and decompensated cirrhotic patients were reported to be safe. Safety profile is a major issue that should not be ignored in the treatment of CHB. Further studies should be done to clarify the adverse effects of NAs and determine follow-up timing and frequency, especially in selected patient populations including those with HIV-coinfection or renal impairment, and pregnant or breastfeeding women.

Prolonged treatment experience can still reveal some unknown adverse effects of drugs. Clinical trial data in different patient populations continue to accumulate in the literature. This review contains updated comprehensive data about the safety profile of NAs used in CHB.

Footnotes

Manuscript source: Invited manuscript

Specialty type: Gastroenterology and hepatology

Country of origin: Turkey

Peer-review report classification

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Conflict-of-interest statement: The authors declare no conflict of interests for this article.

Peer-review started: May 2, 2016

First decision: November 18, 2016

Article in press: December 9, 2016

P- Reviewer: El-Bendary MM, Zhao YL S- Editor: Song XX L- Editor: Filipodia E- Editor: Li D

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PMS-Entecavir – Uses, Side Effects, Interactions

How does this medication work? What will it do for me?

Entecavir belongs to a group of medications called antivirals. It is used to treat people with chronic hepatitis B infection with evidence of active hepatitis B virus replication (reproduction) and evidence of liver damage. It works by stopping the hepatitis B virus from reproducing. There is no cure for hepatitis B infection. Entecavir can decrease the amount of hepatitis B virus in the body and may reduce the damage done to the liver by the hepatitis B virus.

This medication may be available under multiple brand names and/or in several different forms. Any specific brand name of this medication may not be available in all of the forms or approved for all of the conditions discussed here. As well, some forms of this medication may not be used for all of the conditions discussed here.

Your doctor may have suggested this medication for conditions other than those listed in these drug information articles. If you have not discussed this with your doctor or are not sure why you are taking this medication, speak to your doctor. Do not stop taking this medication without consulting your doctor.

Do not give this medication to anyone else, even if they have the same symptoms as you do. It can be harmful for people to take this medication if their doctor has not prescribed it.

What form(s) does this medication come in?

0.5 mg
Each white-to-off-white, triangular, film-coated tablet debossed with “ENT” on one side and “0.5” on the other contains 0.5 mg of entecavir. Nonmedicinal ingredients: crospovidone, ethyl alcohol (present in trace amounts), lactose, magnesium stearate, and microcrystalline cellulose; film coating: polyethylene glycol, polyvinyl alcohol (part. hydrolyzed), talc, and titanium dioxide.

How should I use this medication?

The usual recommended dose for adults and adolescents 16 years of age and older is 0.5 mg once daily. People who have experienced active disease while taking a similar medication called lamivudine may need to take 1 mg once daily. People with reduced kidney function may require a lower dose, as directed by their doctor.

Many things can affect the dose of medication that a person needs, such as body weight, other medical conditions, and other medications. If your doctor has recommended a dose different from the ones listed here, do not change the way that you are taking the medication without consulting your doctor.

Entecavir should be taken on an empty stomach, at least 2 hours before a meal or 2 hours after a meal. The tablet should be swallowed whole with water.

If you miss a dose, take it as soon as possible and continue with your regular schedule. If it is almost time for your next dose, skip the missed dose and continue with your regular dosing schedule. Do not take a double dose to make up for a missed one. If you are not sure what to do after missing a dose, contact your doctor or pharmacist for advice.

Store this medication at room temperature, protect it from light and moisture, and keep it out of the reach of children.

Do not dispose of medications in wastewater (e.g. down the sink or in the toilet) or in household garbage. Ask your pharmacist how to dispose of medications that are no longer needed or have expired.

Who should NOT take this medication?

Do not take entecavir if you are allergic to entecavir or any ingredients of the medication.

What side effects are possible with this medication?

Many medications can cause side effects. A side effect is an unwanted response to a medication when it is taken in normal doses. Side effects can be mild or severe, temporary or permanent.

The side effects listed below are not experienced by everyone who takes this medication. If you are concerned about side effects, discuss the risks and benefits of this medication with your doctor.

The following side effects have been reported by at least 1% of people taking this medication. Many of these side effects can be managed, and some may go away on their own over time.

Contact your doctor if you experience these side effects and they are severe or bothersome. Your pharmacist may be able to advise you on managing side effects.

• diarrhea
• dizziness
• drowsiness
• fatigue
• headache
• heartburn
• nausea
• trouble sleeping
• vomiting

Although most of the side effects listed below don’t happen very often, they could lead to serious problems if you do not seek medical attention.

Check with your doctor as soon as possible if any of the following side effects occur:

• rash
• signs of liver problems, e.g.:
• dark urine
• diarrhea
• loss of appetite
• nausea
• pale stools
• vomiting
• weight loss
• yellowing of the skin or whites of the eyes

Stop taking the medication and seek immediate medical attention if any of the following occur:

• signs of a serious allergic reaction:
• difficulty breathing
• hives
• swelling of the face, lips, eyes, or throat
• symptoms of lactic acidosis:
• abdominal pain
• coldness of arms and legs
• dizziness
• nausea
• shortness of breath
• unusual muscle pain
• vomiting
• weakness

Some people may experience side effects other than those listed. Check with your doctor if you notice any symptom that worries you while you are taking this medication.

Are there any other precautions or warnings for this medication?

Before you begin using a medication, be sure to inform your doctor of any medical conditions or allergies you may have, any medications you are taking, whether you are pregnant or breast-feeding, and any other significant facts about your health. These factors may affect how you should use this medication.

Hepatitis B transmission: Treatment with entecavir does not reduce the risk of passing on hepatitis B to other people through sexual contact and blood transfer. You should continue to take measures to prevent giving hepatitis B to other people (e.g., using condoms) while taking this medication.

Human immunodeficiency virus (HIV): People with HIV infection should discuss with their doctor how this medication may affect their medical condition. If you are taking entecavir for chronic hepatitis B and are not taking any medications for HIV at the same time, some HIV medications that you take in the future may not work as well to treat HIV. Entecavir has not been studied for the treatment of HIV. Your doctor may test you for HIV before beginning treatment with entecavir. If you think that you might have HIV, contact your doctor immediately to get tested.

Kidney function: This medication is removed from the body by the kidneys. If the kidneys are not working properly, entecavir may build up in the body and cause side effects. People with reduced kidney function may need a different dose of the medication. If you have decreased kidney function or kidney disease, discuss with your doctor how this medication may affect your medical condition, how your medical condition may affect the dosing and effectiveness of this medication, and whether any special monitoring is needed.

Lactic acidosis and enlarged liver: Entecavir can cause a rare but serious condition called lactic acidosis (buildup of lactic acid in the blood) together with an enlarged liver and fat in the liver. If you experience any of the following symptoms, call your doctor immediately:

• abdominal pain, swelling, or bloating
• dark-coloured urine
• diarrhea
• fatigue
• feeling unwell
• light-coloured stools
• loss of appetite for several days
• nausea
• shortness of breath
• vomiting
• weakness
• weight loss
• yellow skin or whites of eyes

Your doctor will periodically monitor you and perform laboratory tests to check your liver function.

Lactose intolerance: Entecavir tablets contain lactose. If you have been told that you are intolerant to lactose, contact your doctor before taking this medication.

Liver transplant: The safety and effectiveness of entecavir has not been tested in people who have had a liver transplant. It is not known if entecavir will interact with anti-rejection medications (i.e., cyclosporine, tacrolimus) commonly used after an organ transplant. If you have had a liver transplant, discuss with your doctor how this medication may affect your medical condition, how your medical condition may affect the dosing and effectiveness of this medication, and whether any special monitoring is needed.

Stopping the medication: If you stop taking entecavir, your hepatitis B infection could get worse. Take the medication exactly as prescribed by your doctor, and do not stop taking the medication without checking with your doctor first.

Pregnancy: This medication should not be used during pregnancy unless the benefits outweigh the risks. If you become pregnant while taking this medication, contact your doctor immediately.

Breast-feeding: It is not known if entecavir passes into breast milk. If you are a breast-feeding mother and are taking this medication, it may affect your baby. Talk to your doctor about whether you should continue breast-feeding.

Children: The safety and effectiveness of using this medication have not been established for children less than 16 years of age.

What other drugs could interact with this medication?

There may be an interaction between entecavir and any of the following:

If you are taking any of these medications, speak with your doctor or pharmacist. Depending on your specific circumstances, your doctor may want you to:

• stop taking one of the medications,
• change one of the medications to another,
• change how you are taking one or both of the medications, or
• leave everything as is.

An interaction between two medications does not always mean that you must stop taking one of them. Speak to your doctor about how any drug interactions are being managed or should be managed.

Medications other than those listed above may interact with this medication. Tell your doctor or prescriber about all prescription, over-the-counter (non-prescription), and herbal medications you are taking. Also tell them about any supplements you take. Since caffeine, alcohol, the nicotine from cigarettes, or street drugs can affect the action of many medications, you should let your prescriber know if you use them.

All material copyright MediResource Inc. 1996 – 2021. Terms and conditions of use. The contents herein are for informational purposes only. Always seek the advice of your physician or other qualified health provider with any questions you may have regarding a medical condition. Source: www.medbroadcast.com/drug/getdrug/PMS-Entecavir

Memorial Sloan Kettering Cancer Center

This information from Lexicomp^® explains what you need to know about this medication, including what it’s used for, how to take it, its side effects, and when to call your healthcare provider.

Brand Names: US

Baraclude

Brand Names: Canada

ACCEL-Entecavir; APO-Entecavir; Auro-Entecavir; Baraclude; JAMP-Entecavir; MINT-Entecavir; PMS-Entecavir

Warning

• Hepatitis B has gotten worse when this drug was stopped in some people with hepatitis B. Close follow-up for a few months is needed when therapy is stopped in people who have hepatitis B. Do not stop taking this drug without calling your doctor.
• Rarely, this drug may cause a swollen liver and a buildup of acid in the blood. Sometimes, this may be deadly. The risk may be higher in females, in overweight people, and in people who have taken drugs like this one for a long time.
• If you have HIV that is not being treated, it may become harder to treat after taking this drug. HIV testing needs to be done before taking this drug. Talk with your doctor.

What is this drug used for?

• It is used to treat hepatitis B infection.

What do I need to tell my doctor BEFORE I take this drug?

• If you are allergic to this drug; any part of this drug; or any other drugs, foods, or substances. Tell your doctor about the allergy and what signs you had.

This drug may interact with other drugs or health problems.

Tell your doctor and pharmacist about all of your drugs (prescription or OTC, natural products, vitamins) and health problems. You must check to make sure that it is safe for you to take this drug with all of your drugs and health problems. Do not start, stop, or change the dose of any drug without checking with your doctor.

What are some things I need to know or do while I take this drug?

For all patients taking this drug:

• Tell all of your health care providers that you take this drug. This includes your doctors, nurses, pharmacists, and dentists.
• Have blood work checked as you have been told by the doctor. Talk with the doctor.
• This drug is not a cure for hepatitis infection. Stay under the care of your doctor.
• This drug does not stop the spread of diseases like HIV or hepatitis that are passed through blood or having sex. Do not have any kind of sex without using a latex or polyurethane condom. Do not share needles or other things like toothbrushes or razors.
• If you are 65 or older, use this drug with care. You could have more side effects.
• Tell your doctor if you are pregnant, plan on getting pregnant, or are breast-feeding. You will need to talk about the benefits and risks to you and the baby.

Children:

• If your child’s weight changes, talk with the doctor. The dose of this drug may need to be changed.

What are some side effects that I need to call my doctor about right away?

WARNING/CAUTION: Even though it may be rare, some people may have very bad and sometimes deadly side effects when taking a drug. Tell your doctor or get medical help right away if you have any of the following signs or symptoms that may be related to a very bad side effect:

• Signs of an allergic reaction, like rash; hives; itching; red, swollen, blistered, or peeling skin with or without fever; wheezing; tightness in the chest or throat; trouble breathing, swallowing, or talking; unusual hoarseness; or swelling of the mouth, face, lips, tongue, or throat.
• Signs of liver problems like dark urine, feeling tired, not hungry, upset stomach or stomach pain, light-colored stools, throwing up, or yellow skin or eyes.
• Signs of too much lactic acid in the blood (lactic acidosis) like fast breathing, fast heartbeat, a heartbeat that does not feel normal, very bad upset stomach or throwing up, feeling very sleepy, shortness of breath, feeling very tired or weak, very bad dizziness, feeling cold, or muscle pain or cramps.

What are some other side effects of this drug?

All drugs may cause side effects. However, many people have no side effects or only have minor side effects. Call your doctor or get medical help if any of these side effects or any other side effects bother you or do not go away:

• Headache.
• Feeling dizzy, tired, or weak.
• Upset stomach.

These are not all of the side effects that may occur. If you have questions about side effects, call your doctor. Call your doctor for medical advice about side effects.

You may report side effects to your national health agency.

You may report side effects to the FDA at 1-800-332-1088. You may also report side effects at https://www.fda.gov/medwatch.

How is this drug best taken?

Use this drug as ordered by your doctor. Read all information given to you. Follow all instructions closely.

All products:

• Take on an empty stomach. Take at least 2 hours before or 2 hours after a meal.
• Keep taking this drug as you have been told by your doctor or other health care provider, even if you feel well.
• It is important that you do not miss or skip a dose of this drug during treatment.

Liquid (solution):

• Measure liquid doses carefully. Use the measuring device that comes with this drug.
• Swallow the liquid right from the measuring spoon. Do not mix with water or any other liquid. Rinse the spoon and let air dry after each dose.

What do I do if I miss a dose?

• Take a missed dose as soon as you think about it, on an empty stomach.
• If it is close to the time for your next dose, skip the missed dose and go back to your normal time.
• Do not take 2 doses at the same time or extra doses.
• If you are not sure what to do if you miss a dose, call your doctor.

How do I store and/or throw out this drug?

• Store at room temperature in a dry place. Do not store in a bathroom.
• Keep lid tightly closed.
• Store in the original container to protect from light.
• Keep all drugs in a safe place. Keep all drugs out of the reach of children and pets.
• Throw away unused or expired drugs. Do not flush down a toilet or pour down a drain unless you are told to do so. Check with your pharmacist if you have questions about the best way to throw out drugs. There may be drug take-back programs in your area.

General drug facts

• If your symptoms or health problems do not get better or if they become worse, call your doctor.
• Do not share your drugs with others and do not take anyone else’s drugs.
• Some drugs may have another patient information leaflet. If you have any questions about this drug, please talk with your doctor, nurse, pharmacist, or other health care provider.
• Some drugs may have another patient information leaflet. Check with your pharmacist. If you have any questions about this drug, please talk with your doctor, nurse, pharmacist, or other health care provider.
• If you think there has been an overdose, call your poison control center or get medical care right away. Be ready to tell or show what was taken, how much, and when it happened.

Consumer Information Use and Disclaimer

This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about this medicine. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using this medicine. The use of this information is governed by the Lexicomp End User License Agreement, available at https://www.wolterskluwer.com/en/solutions/lexicomp/about/eula.

Last Reviewed Date

2019-11-12

Copyright

© 2021 UpToDate, Inc. and its affiliates and/or licensors. All rights reserved.

Entecavir – Oral | HealthLink BC

Pronunciation: en-TEK-a-vir

Common Brand Name(s): Baraclude

Important: How To Use This Information

This is a summary and does NOT have all possible information about this product. This information does not assure that this product is safe, effective, or appropriate for you. This information is not individual medical advice and does not substitute for the advice of your health care professional. Always ask your health care professional for complete information about this product and your specific health needs.

Warning

Rarely, entecavir may cause serious (possibly fatal) liver problems and lactic acid build-up in the blood (lactic acidosis). Get medical help right away if you have any of the following symptoms: nausea/vomiting that doesn’t stop, loss of appetite, stomach/abdominal pain, yellowing eyes/skin, dark urine, unusual tiredness/weakness, deep/fast breathing, unusual drowsiness, unusual muscle pain, feeling cold in your arms/legs, fast/irregular heartbeat. These side effects may occur more often in women and obese patients.

Your hepatitis B infection may get worse if you stop taking entecavir. Do not stop this medication without talking to your doctor. Your doctor will do blood tests to check your liver for several months after you stop entecavir.

This medication is not recommended if you have both HIV and hepatitis B and are not receiving effective treatment for HIV. This drug does not treat HIV, and it can cause certain HIV medications to become ineffective. Get an HIV test before starting this medication, and get tested again anytime you may have become infected. Consult your doctor for more details.

Uses

See also Warning section.

Entecavir is used to treat long-term hepatitis B infection. Hepatitis B is an infection of the liver caused by the hepatitis B virus. Long-term infection can cause liver damage, rarely liver cancer, and liver failure. Entecavir helps to decrease the amount of hepatitis B virus in your body. It is unknown if this medication lowers your chance of getting liver cancer or liver damage. Entecavir is an antiviral that belongs to a class of drugs known as hepatitis B virus nucleoside reverse transcriptase inhibitors.

Entecavir is not a cure for hepatitis B. It does not prevent the spread of the virus to others through sexual contact or blood/body fluid contamination (such as sharing used needles).

How To Use

Read the Patient Information Leaflet provided by your pharmacist before you start taking entecavir and each time you get a refill. If you have any questions, ask your doctor or pharmacist.

Take this medication by mouth on an empty stomach (at least 2 hours after a meal and 2 hours before the next meal) as directed by your doctor, usually once daily.

If you are taking entecavir oral liquid, carefully measure your dose with the medicine spoon provided. Do not use a household spoon because you may not get the correct dose. Swallow the medicine directly from the measuring spoon. Do not mix the medication with water or other liquids. Rinse the spoon with water after each use.

The dosage is based on your medical condition and response to treatment. For children, the dosage is also based on weight.

It is very important to continue taking this medication exactly as prescribed by your doctor. Do not skip any doses.

This medication works best when the amount of drug in your body is kept at a constant level. Take this drug at evenly spaced intervals. To help you remember, take it at the same time each day.

Do not take more or less of this drug than prescribed or stop taking it even for a short time unless directed to do so by your doctor. Doing so may cause the amount of virus to increase, make the infection more difficult to treat (resistant), or worsen side effects. See also Warning section.

Tell your doctor if your condition does not get better or if it gets worse.

Side Effects

See also Warning section.

Headache, tiredness, dizziness, or nausea may occur. If any of these effects last or get worse, tell your doctor or pharmacist promptly.

Remember that your doctor has prescribed this medication because he or she has judged that the benefit to you is greater than the risk of side effects. Many people using this medication do not have serious side effects.

A very serious allergic reaction to this drug is rare. However, get medical help right away if you notice any symptoms of a serious allergic reaction, including:

• rash
• itching/swelling (especially of the face/tongue/throat)
• severe dizziness
• trouble breathing

This is not a complete list of possible side effects. If you notice other effects not listed above, contact your doctor or pharmacist.

In the US –

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088 or at www.fda.gov/medwatch.

In Canada – Call your doctor for medical advice about side effects. You may report side effects to Health Canada at 1-866-234-2345.

Precautions

Before taking entecavir, tell your doctor or pharmacist if you are allergic to it; or if you have any other allergies. This product may contain inactive ingredients, which can cause allergic reactions or other problems. Talk to your pharmacist for more details.

Before using this medication, tell your doctor or pharmacist your medical history, especially of:

• HIV infection
• kidney disease
• other hepatitis B drugs taken in the past

This drug may make you dizzy. Alcohol or marijuana (cannabis) can make you more dizzy. Do not drive, use machinery, or do anything that needs alertness until you can do it safely. Avoid alcoholic beverages. Alcohol may also worsen liver problems. Talk to your doctor if you are using marijuana (cannabis).

Before having surgery, tell your doctor or dentist about all the products you use (including prescription drugs, nonprescription drugs, and herbal products).

To decrease your risk of spreading hepatitis B to others, always use an effective barrier method (latex or polyurethane condoms/dental dams) during all sexual activity. Consult your doctor or pharmacist for more details.

During pregnancy, this medication should be used only when clearly needed. It is not known if this medication helps to prevent the hepatitis B virus from passing from the mother to the baby. Discuss the risks and benefits with your doctor.

It is unknown if this drug passes into breast milk. Consult your doctor before breast-feeding. If you also have HIV infection, do not breast-feed because breast milk can transmit HIV.

Drug Interactions

Drug interactions may change how your medications work or increase your risk for serious side effects. This document does not contain all possible drug interactions. Keep a list of all the products you use (including prescription/nonprescription drugs and herbal products) and share it with your doctor and pharmacist. Do not start, stop, or change the dosage of any medicines without your doctor’s approval.

Overdose

If someone has overdosed and has serious symptoms such as passing out or trouble breathing, call 911. Otherwise, call a poison control center right away. US residents can call their local poison control center at 1-800-222-1222. Canada residents can call a provincial poison control center.

Notes

Do not share this medication with others.

Lab and/or medical tests (such as liver tests, virus levels) should be done while you are taking this medication. Keep all medical and lab appointments.

Missed Dose

If you miss a dose, take it as soon as you remember. If it is near the time of the next dose, skip the missed dose. Take your next dose at the regular time. Do not double the dose to catch up.

Storage

Store at room temperature away from light and moisture. To protect from light, store the bottle of medication in the original carton. Do not store in the bathroom. Keep all medications away from children and pets.

Do not flush medications down the toilet or pour them into a drain unless instructed to do so. Properly discard this product when it is expired or no longer needed. Consult your pharmacist or local waste disposal company.

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Entecavir instructions for use: indications, contraindications, side effects – description Entecavir Film-coated tablets (46507)

When treating with nucleoside analogues, incl. with entecavir, in the form of monotherapy and in combination with antiretroviral drugs, cases of lactic acidosis and severe hepatomegaly with steatosis have been described, sometimes leading to the death of the patient.

Symptoms that may indicate the development of lactic acidosis: general fatigue, nausea, vomiting, abdominal pain, sudden weight loss, shortness of breath, rapid breathing, muscle weakness.

Risk factors are female sex, obesity, long-term use of nucleoside analogs, hepatomegaly. If these symptoms appear or laboratory confirmation of lactic acidosis is obtained, treatment with the drug should be discontinued.

Cases of exacerbation of hepatitis after discontinuation of antiviral therapy, incl. entecavir. Most of these cases resolved without treatment. However, severe exacerbations may develop, incl. fatal. The causal relationship of these exacerbations to treatment withdrawal is unknown.After stopping treatment, it is necessary to periodically monitor liver function. Antiviral therapy can be resumed if necessary.

It should be borne in mind that the use of entecavir in patients with HIV co-infection who are not receiving antiretroviral therapy may be at risk of developing resistant strains of HIV. Entecavir has not been studied for the treatment of HIV infection and is not recommended for such use.

There is a high risk of developing serious side effects from the liver, in particular in patients with decompensated liver disease class C according to the Child-Pugh classification.These patients are also more at risk of developing lactic acidosis and specific renal side effects such as hepatorenal syndrome. In this regard, patients should be carefully monitored for clinical signs of lactic acidosis and renal dysfunction, as well as appropriate laboratory tests should be carried out in this group of patients (liver enzyme activity, blood lactic acid concentration, serum creatinine concentration).

The presence of hepatitis B virus resistance mutations to lamivudine increases the risk of developing entecavir resistance. Therefore, in lamivudine-resistant patients, frequent viral load monitoring and, if necessary, appropriate testing for resistance mutations is required.

Correction of the dosage regimen is recommended for patients with impaired renal function.

The safety and efficacy of entecavir in liver transplant patients is unknown.Renal function should be closely monitored before and during treatment with entecavir in patients undergoing liver transplantation and receiving immunosuppressants that may affect renal function, such as cyclosporine and tacrolimus.

Entecavir Sandoz instructions for use: indications, contraindications, side effects – description Entecavir Sandoz tab., Cover. film coating, 0.5 mg: 30 pcs. (47971)

indications and contraindications, composition and dosage – Pharmacy Mos

Entecavir – instructions for use

Lactic acidosis / severe hepatomegaly with steatosis

In the treatment of nucleoside analogues, cases of lactic acidosis and severe hepatomegaly with steatosis, sometimes leading to the death of the patient, have been described. Since entecavir is a nucleoside analogue, the risk of developing this complication cannot be excluded when using it.

Symptoms that may indicate the development of lactic acidosis: general fatigue, nausea, vomiting, abdominal pain, sudden weight loss, shortness of breath, rapid breathing, muscle weakness. In severe, sometimes fatal cases, the development of lactic acidosis has been associated with pancreatitis, liver failure / hepatic steatosis, renal failure, and hyperlactatemia. Risk factors are female sex, obesity, long-term use of nucleoside analogs, hepatomegaly.

Treatment with nucleoside analogs should be discontinued if symptomatic hyperlactatemia and metabolic acidosis / lactic acidosis develop, progressive hepatomegaly, or a rapid increase in aminotransferase levels. Care must be taken when using nucleoside analogs to treat any patient (especially obese women) with hepatomegaly, hepatitis, or other known risk factors for liver damage and hepatic steatosis (including the use of certain drugs and alcohol use).Careful clinical and laboratory monitoring is required when treating such patients.

In order to distinguish an increase in aminotransferase activity as evidence of treatment success from an increase potentially associated with lactic acidosis, the physician should ensure that changes in ALT activity are associated with an improvement in other laboratory markers of chronic hepatitis B.

Exacerbations of hepatitis

Spontaneous exacerbations Chronic hepatitis B infections are common and are characterized by transient increases in serum ALT.After the initiation of antiviral therapy, in some patients, an increase in ALT activity is possible against the background of a decrease in the level of HBV DNA in the blood serum. In most cases, exacerbation of hepatitis developed during the first 4–5 weeks of entecavir therapy. In patients with compensated liver disease, this increase in ALT activity is usually not accompanied by an increase in serum bilirubin concentration or liver failure. Patients with advanced liver disease or cirrhosis are at increased risk of liver decompensation.Careful clinical and laboratory monitoring should be carried out in the treatment of such patients.

Cases of exacerbation of hepatitis were also reported in patients who stopped taking medications for the treatment of hepatitis B. Exacerbations after discontinuation of treatment, as a rule, are associated with an increase in HBV DNA levels, in most cases do not lead to decompensation of liver function and stop spontaneously. However, severe exacerbations, including fatal ones, have been reported.

Among patients who had not previously received nucleoside analogs who were prescribed entecavir, an exacerbation developed on average within the first 23-24 weeks after discontinuation of the drug, in most cases in HBeAg-negative patients.Liver function should be monitored periodically for at least 6 months after stopping hepatitis therapy. If necessary, resuming hepatitis B medications may be warranted.

Patients with hepatitis B / HIV co-infection

It should be borne in mind that when prescribing entecavir to patients with HIV co-infection who are not receiving highly active antiretroviral therapy (HAART), there may be a risk of developing resistant strains of HIV. Therefore, entecavir should not be used in patients with hepatitis B / HIV co-infection who are not receiving HAART.Entecavir has not been studied as a treatment for HIV infection and is not recommended for such use.

Patients with combined hepatitis B / hepatitis C / hepatitis D infection

There is no data on the efficacy of entecavir in patients with combined hepatitis B / hepatitis C / hepatitis D infections.

Patients with decompensated liver damage

There is a high risk of developing serious side effects from the liver, in particular in patients with decompensated liver disease class C according to the Child-Pugh classification.These patients are also more at risk of developing lactic acidosis and specific renal side effects such as hepatorenal syndrome. In this regard, patients should be carefully monitored for clinical signs of lactic acidosis and renal dysfunction, as well as appropriate laboratory tests should be carried out in this group of patients (activity of “liver” enzymes, concentration of lactic acid in the blood, concentration of creatinine in blood serum) …

Lamivudine-resistant patients

Lamivudine-resistant patients are at a higher risk of later developing entecavir resistance than patients without lamivudine resistance. The likelihood of developing genotypic resistance to entecavir after 1, 2, 3, 4 and 5 years of treatment in studies in lamivudine-resistant patients was 6%, 15%, 36%, 47% and 51%, respectively. This requires frequent monitoring of viral load and appropriate testing for resistance in lamivudine-resistant patients.In patients with a suboptimal virologic response after 24 weeks of entecavir treatment, consideration should be given to modifying the therapy regimen. When initiating therapy for patients with documented HBV resistance to lamivudine, entecavir should be preferred in combination with another antiviral drug (not cross-resistant with lamivudine or entecavir) over entecavir alone.

The presence of HBV resistance to lamivudine is associated with an increased risk of developing entecavir resistance, regardless of the degree of liver dysfunction.In patients with decompensated liver disease, virologic breakthrough may be associated with serious clinical complications of liver disease. Thus, in lamivudine-resistant patients with decompensated liver disease, the use of entecavir in combination with another antiviral drug that does not cross-resistance with lamivudine or entecavir is preferred over entecavir alone.

Patients with impaired renal function

For patients with impaired renal function, a dosage adjustment is recommended.The recommendations proposed are based on the extrapolation of limited data, and the safety and efficacy of these regimens has not been evaluated clinically. Therefore, in patients with impaired renal function, the virological response should be carefully monitored.

Patients undergoing liver transplantation

The safety and efficacy of entecavir in patients undergoing liver transplantation are unknown. Renal function should be carefully monitored before and during treatment with entecavir in patients who have undergone liver transplantation and are receiving immunosuppressants that may affect renal function, such as cyclosporine and tacrolimus

Baraclude: description, prescription, instruction

Baraclude

Analogs (generics, synonyms)

Active ingredient

Entecavirum

Pharmacological group

Antiviral (excluding HIV) drugs

Recipe

International:

Rp.: “Baraclude” 0.5 mg
D.t.d. No. 30 in tabl.
S. 1 tablet once a day

Russia:

Rp .: Entecaviri 1 mg
D.t.d. No. 30 in tabl.
S. 1 tablet once a day

Prescription form 107-1 / y

Pharmacological action

Antiviral drug, is an analogue of guanosine nucleoside with potent and selective activity against hepatitis B virus (HBV) polymerase. Entecavir is phosphorylated to form active triphosphate with an intracellular half-life of 15 hours.The intracellular concentration of entecavir triphosphate is directly related to the extracellular level of entecavir, and there is no significant accumulation of the drug after the initial “plateau” level. By competing with the natural substrate, deoxyguanosine triphosphate, entecavir triphosphate inhibits all 3 functional activities of viral polymerase: 1) priming of HBV polymerase, 2) reverse transcription of a negative strand from pregenomic mRNA, and 3) synthesis of a positive HBV DNA strand. Entecavir triphosphate is a weak inhibitor of cellular DNA polymerases α, β and δ with Ki 18-40 μM.In addition, at high concentrations of entecavir triphosphate and entecavir, no side effects were observed with respect to γ ​​polymerase and DNA synthesis in the mitochondria of HepG2 cells.

Pharmacodynamics

There is no data for this section. We are currently processing information, please come back later.

Pharmacokinetics

There is no data for this section. We are currently processing information, please come back later.

Method of application

For adults:

Baraklud is taken orally.The tablets must be taken on an empty stomach (the interval between meals and the drug should be 2 hours).
Patients over 16 years old are recommended to take 0.5 mg of the drug per day (for 1 dose). Patients in whom lamivudine therapy is ineffective are usually recommended to take 1 mg of entecavir per day (in 1 dose).
The time of therapy is determined by a specialist, taking into account the data of laboratory and clinical parameters. Treatment can take over a year.
In case of impaired renal clearance, the dose of entecavir must be adjusted (especially in patients who are indicated for hemodialysis or prolonged peritoneal dialysis).
Standard doses are recommended for clearance greater than 50 ml / min.
With a clearance of more than 30 ml / min, it is desirable to increase the time between taking the usual doses up to 48 hours (thus, patients take 0.5 mg of Baraklud once every 2 days, or 1 mg of entecavir (if they are insensitive to lamivudine therapy) every 48 hours ).
When clearance rates are more than 10 ml / min, the interval between taking standard doses is increased to 72 hours.
Patients who are indicated for hemodialysis or prolonged peritoneal dialysis should take entecavir (in a standard single dose) once every 5-7 days (as a rule, the drug is prescribed after a hemodialysis session).
In case of insufficient liver function, no dose adjustment of entecavir should be performed.
Some cases have been described when, after discontinuation of therapy, patients experienced an exacerbation of hepatitis (a causal relationship with discontinuation of entecavir has not been established). After discontinuation of the drug, it is necessary to monitor liver function and, if necessary, continue therapy.
It is necessary to monitor the functional activity of the kidneys during therapy with the drug Baraklud (especially in persons whose renal function is reduced, as well as in patients receiving therapy that may affect renal clearance).

Readings

Chronic hepatitis B in adults with:
– compensated liver damage and the presence of viral replication, increased levels of serum transaminase activity (ALT or ACT) and histological signs of liver inflammation and / or fibrosis;
– decompensated liver damage.

Contraindications

– hypersensitivity to entecavir or any other component of the drug;
– rare hereditary lactose intolerance, lactase deficiency or glucose-galactose malabsorption;
– children under 18 years of age.

Special instructions

There is no data for this section. We are currently processing information, please come back later.

Side effects

From the digestive system: rarely (≥1 / 1000, <1/100) - diarrhea, dyspepsia, nausea, vomiting.

From the side of the central nervous system: often (≥1 / 100, <1/10) - headache, fatigue; rarely (≥1 / 1000, <1/100) - insomnia, dizziness, drowsiness.

Post-marketing data (frequency cannot be determined)

From the immune system: anaphylactoid reaction

From the skin and subcutaneous tissue: alopecia, rash.

From the liver: increased activity of transaminases.

Metabolic: lactic acidosis (general fatigue, nausea, vomiting, abdominal pain, sudden weight loss, shortness of breath, rapid breathing, muscle weakness), especially in patients with decompensated liver damage.

In addition, in patients with decompensated liver damage, the following additional side effects were noted: often – a decrease in the concentration of bicarbonate in the blood, an increase in the activity of ALT and the concentration of bilirubin by more than 2 times compared with VGN, the concentration of albumin is less than 2.5 g / dl, increase in lipase activity by more than 3 times compared to normal, platelet concentration below 50,000 / mm3; rarely renal failure.
Contraindications

Overdose

There is no data for this section. We are currently processing information, please come back later.

Drug interactions

There is no data for this section. We are currently processing information, please come back later.

Form of issue

Film-coated tablets, 0.5 mg: triangular, coated white or off-white, marked “BMS” on one side and “1611” on the other.

Film-coated tablets, 1 mg: triangular, pink-coated, labeled “BMS” on one side and “1612” on the other.

ENTEKAVIR tablets – instructions for use, price, dosages, analogs, contraindications

Active ingredient

– entecavir

Composition and release form of the drug

Film-coated tablets white , biconvex, capsule-shaped; on the cross section of the tablet, the core is white.

Excipients: lactose monohydrate – 139.94 mg, microcrystalline cellulose – 49 mg, crospovidone type B – 4 mg, povidone K30 – 5 mg, magnesium stearate – 2 mg.

Composition of the film shell : polyvinyl alcohol – 40%, titanium dioxide (E171) – 20/24%, macrogol – 20.2%, talc – 14.8%.

10 pcs.- blister packs (3) – cardboard packs.

Pharmacological action

Antiviral agent, analogue of guanosine nucleoside with potent and selective activity against hepatitis B virus (HBV) polymerase.

Entecavir is phosphorylated to form an active triphosphate with an intracellular half-life of 15 hours. The intracellular concentration of entecavir triphosphate is directly related to the extracellular level of entecavir, and there is no significant accumulation of the drug after the initial plateau level.By competing with the natural substrate, deoxyguanosine triphosphate, entecavir triphosphate inhibits all 3 functional activities of viral polymerase: 1) priming of HBV polymerase, 2) reverse transcription of a negative strand from pregenomic mRNA, and 3) synthesis of a positive HBV DNA strand. Entecavir triphosphate is a weak inhibitor of cellular DNA polymerases α, β and δ with Ki 18-40 μM. In addition, at high concentrations of entecavir triphosphate and entecavir, no side effects were observed with respect to γ ​​polymerase and DNA synthesis in the mitochondria of HepG2 cells.

Related news

Pharmacokinetics

In healthy people, absorption of entecavir is fast, C _max in blood plasma is determined after 0.5-1.5 hours max and AUC. The equilibrium state is achieved after 6-10 days of oral administration 1 time / day, while the plasma concentration increases by about 2 times. C _max and C _min in plasma in equilibrium state were 4.2 and 0.3 ng / ml, respectively, when taking the drug at a dose of 500 μg, 8.2 and 0.5 ng / ml, respectively, when taking a dose of 1 mg. When entecavir was taken orally at a dose of 500 μg, both with food with a high fat content and with a low one, there was a minimal delay in absorption (1-1.5 h when taken with food and 0.75 hours when taken on an empty stomach), a decrease in C _max by 44-46 % and a decrease in AUC by 18-20%.

V _d entecavir exceeded the total volume of water in the body, which indicates a good penetration of the drug into the tissues.The binding of entecavir to human plasma proteins in vitro is about 13%.

Entecavir is not a substrate, inhibitor or inducer of isoenzymes of the P450 system. After administration of labeled C-entecavir ¹⁴ to humans and rats, no oxidized or acetylated metabolites were detected, and phase II metabolites (glucuronides and sulfates) were detected in small amounts.

After reaching C _max , the concentration of entecavir in plasma decreased biexponentially, while T _1/2 was 128-149 hours.When taken 1 time / day, the concentration (cumulation) of the drug increased by 2 times, that is, the effective T _1/2 was approximately 24 hours.

Entecavir is excreted mainly by the kidneys, and 62-73% of the dose is determined unchanged in the urine in the equilibrium state. Renal clearance is independent of dose and ranges from 360 to 471 ml / min, which indicates glomerular filtration and tubular secretion of entecavir.

Indications

Chronic hepatitis B in adults with compensated liver damage and the presence of viral replication, increased levels of serum transaminase (ALT or ACT) activity and histological signs of liver inflammation and / or fibrosis, with decompensated liver damage.

Contraindications

Children and adolescents under 18 years of age; hypersensitivity to entecavir.

Dosage

Taken orally. The dose is 500-1000 mcg 1 time / day. The frequency of admission depends on the degree of impaired renal function, indications in the history of therapy with nuleoside drugs, liver condition.

Side effects

From the digestive system : rarely – diarrhea, dyspepsia, nausea, vomiting; possibly – an increase in the activity of transaminases.

From the side of the central nervous system: often – headache, fatigue; rarely – insomnia, dizziness, drowsiness.

From the immune system: possibly an anaphylactoid reaction.

Skin and subcutaneous tissue disorders: possibly – alopecia, rash.

From the metabolic side: possibly – lactic acidosis (general fatigue, nausea, vomiting, abdominal pain, sudden weight loss, shortness of breath, rapid breathing, muscle weakness), especially in patients with decompensated liver damage.

In addition, in patients with decompensated liver damage, the following additional side effects were noted: often – a decrease in the concentration of bicarbonate in the blood, an increase in the activity of ALT and the concentration of bilirubin by more than 2 times compared with VGN, the concentration of albumin is less than 2.5 g / dL, an increase in activity lipase more than 3 times compared with the norm, the platelet concentration is below 50,000 / μl; rarely renal failure.

Drug interaction

Since entecavir is excreted mainly by the kidneys, with the simultaneous administration of entecavir and drugs that cause impaired renal function or compete at the level of tubular secretion, an increase in serum concentration of entecavir or these drugs is possible.

The interaction of entecavir with other drugs that are excreted by the kidneys or affect renal function has not been studied. With the simultaneous use of entecavir with such drugs, the patient’s condition should be carefully monitored.

Special instructions

When treating with nucleoside analogues, incl. with entecavir, in the form of monotherapy and in combination with antiretroviral drugs, cases of lactic acidosis and severe hepatomegaly with steatosis have been described, sometimes leading to the death of the patient.

Symptoms that may indicate the development of lactic acidosis: general fatigue, nausea, vomiting, abdominal pain, sudden weight loss, shortness of breath, rapid breathing, muscle weakness.

Risk factors are female sex, obesity, long-term use of nucleoside analogs, hepatomegaly. If these symptoms appear or laboratory confirmation of lactic acidosis is obtained, treatment with the drug should be discontinued.

Cases of exacerbation of hepatitis after discontinuation of antiviral therapy, incl.h. entecavir. Most of these cases resolved without treatment. However, severe exacerbations may develop, incl. fatal. The causal relationship of these exacerbations to treatment withdrawal is unknown. After stopping treatment, it is necessary to periodically monitor liver function. Antiviral therapy can be resumed if necessary.

It should be borne in mind that the use of entecavir in patients with HIV co-infection who are not receiving antiretroviral therapy may be at risk of developing resistant strains of HIV.Entecavir has not been studied for the treatment of HIV infection and is not recommended for such use.

There is a high risk of serious side effects from the liver, in particular, in patients with decompensated liver disease class C according to the Child-Pugh classification. These patients are also more at risk of developing lactic acidosis and specific renal side effects such as hepatorenal syndrome. In this regard, patients should be carefully monitored for clinical signs of lactic acidosis and renal dysfunction, as well as appropriate laboratory tests should be carried out in this group of patients (liver enzyme activity, blood lactic acid concentration, serum creatinine concentration).

The presence of hepatitis B virus resistance mutations to lamivudine increases the risk of developing entecavir resistance. Therefore, in lamivudine-resistant patients, frequent viral load monitoring and, if necessary, appropriate testing for resistance mutations is required.

Correction of the dosage regimen is recommended for patients with impaired renal function.

The safety and efficacy of entecavir in liver transplant patients is unknown.Renal function should be closely monitored before and during treatment with entecavir in patients undergoing liver transplantation and receiving immunosuppressants that may affect renal function, such as cyclosporine and tacrolimus.

Pregnancy and lactation

There have been no adequate and well-controlled studies in pregnant women. Use during pregnancy is possible only in cases where the expected benefit of therapy to the mother outweighs the potential risk to the fetus.

There are no data on the elimination of entecavir in breast milk. During the treatment period, breastfeeding is not recommended.

The description of ENTEKAVIR is based on the officially approved instructions for use and approved by the manufacturer.

The price information provided for the drugs does not constitute an offer to sell or buy a product. The information is intended solely for comparing prices in inpatient pharmacies operating in accordance with Article 55 of the Federal Law “On Circulation of Medicines”.

Found an error? Select it and press Ctrl + Enter.

Treatment of chronic hepatitis B with Baraclude

Siegbert Rossol, gastroenterologist, specialist in internal medicine

Since 2006 he has been the chief physician of the Nordwest Medical Clinic.

More about the specialist →

Dear patient! Your doctor has prescribed Baraclude for you for chronic hepatitis B.When your doctor told you the diagnosis of chronic hepatitis B, you were obviously surprised and unprepared, or perhaps fearful. You have to start treatment, and at the same time you have a lot of questions.

With this article, we would like to answer your questions about Baraclude treatment as well as chronic hepatitis B and support all patients in the successful treatment.

To ensure that you are safe and follow the course of treatment, read the information and instructions for treatment with Baraclude very carefully to the end.If you have any questions, contact your doctor. We wish you all the best and successful therapy.

HEPATITIS B – WHAT YOU SHOULD KNOW b

What is Hepatitis B?

If the doctor diagnoses chronic hepatitis B, then the blood test showed hepatitis B virus (HBV) infection

HBV is a virus that specifically infects the human liver: this virus uses liver cells to reproduce. The body counteracts this with the help of its own immune system: the body’s own defense reaction against a foreign virus causes inflammation of the liver – hepatitis.

Chronic liver inflammation caused by the virus damages the liver and can lead to serious health consequences over time.

How is hepatitis B transmitted?

• The hepatitis B virus (HBV) is widespread and very common worldwide: the World Health Organization estimates that around 2 billion people are infected with the virus worldwide. At least 350 million people suffer from chronic hepatitis B infection.
• Hepatitis B is highly contagious and the likelihood of infection depends on various factors. For example, there are countries in which the virus is especially widespread and is often transmitted from mother to child at birth. In contrast, in countries that have introduced a vaccination program, prevalence is declining.
• Certain occupations and living conditions may increase the risk of illness if a person is not vaccinated against hepatitis B. For example, contact with contaminated medical equipment, contact with needles from infected drug addicts, and frequent sex partner changes.

In everyday life, hepatitis B is transmitted primarily through direct contact, blood stains or skin lesions. Outside the body, the virus is able to remain alive for at least 7 days.

Why does this infection become chronic?

• Some people who have been exposed to the virus recover from acute infection without consequences. After that, they are no longer contagious to others. However, in 5-10% of infected people, the virus remains in the blood and, accordingly, in the body for a long time (i.e.e. chronic hepatitis B develops).
• Hepatitis B is considered chronic if the infection lasts longer than six months.

What effect does hepatitis B have on the liver

The liver is a vital organ that performs a number of functions in the body, for example, protecting against infections and diseases, assimilating food, and neutralizing foreign substances.

• Chronic inflammation caused by the hepatitis B virus can damage and kill liver cells.In some cases, this process can lead to scarring (liver fibrosis), which after a long time can turn into cirrhosis of the liver.
• Depending on how long the virus is present and multiplies unhindered in the body, fibrosis and / or cirrhosis of the liver can lead to liver failure and sometimes liver cancer.
• Often, patients do not feel liver damage as a result of chronic hepatitis B. A specialist doctor makes special tests, with the help of which he can assess the condition of the patient’s liver.Based on these results, he also determines the necessary therapeutic measures.
• Modern antiviral drugs can now contain the virus and prevent long-term liver damage.

How does the therapy protect the liver?

For most people with chronic hepatitis B, full recovery is not possible and the disease can last a lifetime.

• It is now known that possible long-term liver damage in chronic hepatitis B is also associated with the amount of virus present in the body.
• Antiviral drugs can keep the virus from multiplying in most people on treatment. Strong and long-term reductions in virus levels also reduce the risk of long-term damage such as cirrhosis and liver cancer.

Prolonged reduction of the virus content under the influence of drug treatment improves the prognosis of the disease and allows you to lead a normal life.

How long is the therapy effective?

• An important condition for the long-term effect of treatment is the regular and correct intake of antiviral pills.Irregular reception or skipping receptions for forgetfulness reduces the level of the active substance in the body. This can lead to the resumption of the rapid multiplication of the virus.
• If the virus manages to multiply again during this process, new, treatment-resistant variants of the virus can form. If they become entrenched in the body, this will reduce the effectiveness of therapy and limit the possibility of treatment in the future.

Antiviral therapy lowers the virus in the blood and may protect the liver from possible long-term damage.To keep the virus low in the body for a long time, it is important to take medication regularly and as prescribed.

TREATMENT OF HEPATITIS WITH BARACLUDE

What is Baraclude

• Baraclude is an antiviral drug from the group of so-called nucleoside analogs. Each film-coated tablet of the drug contains 0.5 of the active ingredient, which is called entecavir.

Who Can Get Baraclude Treatment

• Baraclude is used to treat chronic (long-term) hepatitis B viral infection in adults.
• Treatment with this drug is suitable for patients with liver damage who have liver

– not yet fully functional (compensated liver disease)

– not fully functional anymore (decompensated liver disease)

What does Baraclude look like

• Baraclude are white or off-white triangular film-coated tablets.On one side of the tablets, the marking “BMS” is embossed, on the other “1611”.
• Baraclude is supplied as film-coated tablets (white 0.5 mg, pink 1 mg) and as an oral solution (0.05 mg / ml). The coated tablets are supplied in cardboard boxes.

How to take Baraclude

• Baraclude taken orally once a day

How Baraclude Works

• Baraclude is capable of directly inhibiting the multiplication of hepatitis B virus in the body.Thus, the liver damage caused by the virus can be reduced and its condition improved.
• The mechanism of action is based on the fact that Baraclude blocks the viral enzyme (HBV DNA polymerase). As a result, the copying of the hereditary material of the virus in the liver cells stops.
• Baraclude forms the so-called false building block (nucleoside analog) immediately prior to copying the viral genome. As a result, during the synthesis of the virus genome chain, its premature termination occurs.The reproduction of the virus is disrupted or completely stops.

Meals and Baraclude Medication

• In most cases, you can take Baraklud with or without food
  • If the patient was previously treated with a drug containing lamivudine, then the following should be considered: if the patient is transferred to Baraclude because treatment with lamivudine was ineffective, then Baraclude should be taken once a day on an empty stomach. Fasting means: at least two hours after a meal or at least two hours before the next meal.
  • If liver disease has gone very far, your doctor may also recommend taking Baraclude on an empty stomach.

What to do in case of a reception error?

• If you take more Baraclude than you should: Call your doctor right away.
• If you forget to take Baraclude:

Take your medicine as soon as possible and take the next dose at the right time.

If it is almost time for the next dose, there is no need to make up for the missed dose. In this case, wait and take the next dose at the appropriate time.

If you missed a previous dose, avoid taking a double dose.

• End of therapy:

Do not stop taking Baraclude on your own without talking to your doctor; in some cases, very bad symptoms of hepatitis may occur after you stop taking Baraclude.

Treatment should not be interrupted without consulting a doctor. After the end of therapy, the doctor will regularly monitor the patient’s condition for several months. At the same time, he will take blood tests. It is necessary to inform the attending physician about all changes and symptoms that will be noticed after the end of treatment.

What to look for before taking Baraclude ?

Do not take Baraclude if you are hypersensitive (allergic) to entecavir or any other component of Baraclude.Before you start taking Baraclude, you must tell your doctor if you have an intolerance to certain types of sugars:

• Baraclude tablets contain lactose (milk sugar)
• Baraclude Solution contains maltitol (a sugar substitute).

It is also necessary to inform the doctor in the following situations, since in such cases special care is required when using the drug Baraclude:

• If you have ever suffered from liver disease (for example, impaired liver function)
• If the liver is no longer fully functioning
• If you also have HIV (Human Immunodeficiency Virus): Baraclude is not intended to treat HIV infection.You should not take Baraclude to treat hepatitis B virus infection unless you are taking HIV medications at the same time. Otherwise, the effectiveness of subsequent HIV treatment may be reduced.

Taking Baraclude with other medicines.

• Tell your doctor about any other medications you are taking or recently taken, including over-the-counter medications.

Does Baraclude Protect Against Hepatitis B Transmission?

• No, Baraclude cannot prevent the transmission of hepatitis B virus (HBV) to others through sexual contact or body fluids (including infected blood).

People at risk of hepatitis B infection (HBV ) can protect themselves with HBV vaccination

Baraclude and pregnancy

Tell your doctor if you are pregnant or want to become pregnant.

• There is no data available on the safety of using Baraclude during pregnancy. Do not take Baraclude during pregnancy unless strongly advised by your doctor.
• Use a safe method of contraception while taking Baraclude to prevent pregnancy.
• Breastfeeding should be avoided during treatment with Baraclude because it is not known whether the active ingredient of the drug passes into breast milk.

Baraclude does not protect against virus transmission. Take appropriate precautions to avoid spreading the infection to others

Baraclude and driving ability.

Dizziness, fatigue (exhaustion) and drowsiness, which are common side effects of Baraclude treatment, can affect the ability to drive and operate machinery.

• If in doubt, consult your doctor.

What are the possible side effects?

Like all medicines, Baraclude can cause side effects, although not everybody gets them.

The following side effects have been reported with Baraclude treatment:

• Often (≥1 out of 100 patients):

Headache, insomnia, exhaustion (very fatigue), dizziness, drowsiness, vomiting, diarrhea, nausea, indigestion (dyspepsia) and elevated levels of liver enzymes in the blood.

• Sometimes (≥1 in 100 patients):

Skin rash, hair loss

• Rare (≥1 in 10,000 patients):

Severe allergic reactions.

• In some cases, lactic acidosis was noted, often associated with liver failure, other severe conditions of the body, or with the simultaneous administration of other drugs. These rare, however, very severe effects have sometimes been fatal.Symptoms such as nausea, vomiting, and abdominal pain may be accompanied by the development of lactic acidosis.

Baraclude belongs to a group of drugs that can cause lactic acidosis (excess lactic acid in the blood), as well as enlargement of the liver. Lactic acidosis is more common in women, especially those who are overweight. During treatment, the doctor regularly examines the subject of lactic acidosis.

How to store Baraclude ?

• Keep Baraclude out of the reach of children
• It is forbidden to use Baraclude after the expiration date stated on the vial label, blister pack, or carton (original packaging) after the words Verwendbar bis (use before): (or EXP (expiry date): on the blister pack).The expiration date is the last day of the month.
• Store Baraclude in its original packaging:

• Blister:

At a temperature not exceeding 30 ° C.

At a temperature not exceeding 25 ° C. Keep the bottle tightly closed

• Baraclude Solution:
  • You can eat anything – there are no specific dietary recommendations for hepatitis B.
  • Whenever possible, try to maintain a balanced diet to strengthen the immune system and improve your well-being.
  • It is recommended to monitor the weight
  • If you already have severe liver damage, your doctor will advise you on diet and advise you to seek the advice of a dietitian.
  • Avoid drinking alcohol as it puts additional strain on your liver.
  • Smoking cessation recommended: Smoking reduces the ability of the immune system to fight the hepatitis virus. When combined with hepatitis B infection, smoking increases the risk of liver cancer.
  • Exercising at the right level of activity improves your health and helps you maintain a healthy weight.
  • Live mindfully: make sure you have enough time to sleep and rest.
  • To better deal with stress, it may be worth learning relaxation techniques such as meditation and yoga.
  • Choose a quiet moment for the daily single dose of pills in your daily routine
  • Store Baraclude in an easily accessible place that is part of your daily routine, such as near a coffee maker or next to toothpaste.
  • Set your alarm clock, mobile phone or smartphone to a regular reminder to take the drug.
  • The hepatitis B virus is transmitted primarily through blood, since it contains the highest concentration of the virus.
  • The virus may be present in other body fluids such as semen, vaginal fluid, or saliva.
  • Do not share hygiene items, such as a toothbrush or straight razor with other people in your household
  • The risk of infection may vary, for example, depending on the viral load.
  • If you are pregnant, you have the opportunity to protect your baby from infection. Your baby may be vaccinated against hepatitis B at birth. Your doctor will tell you more about this.
  • Convince your next of kin to get tested by a doctor for hepatitis B infection and get vaccinated if necessary.
  • You can discuss questions and concerns about you, for example, related to your illness or treatment, during a visit to the doctor for the purpose of examination.
  • Before this visit, write down the questions you would like to ask. At home, you can keep a patient diary as a reminder.
  • Talk with your doctor about test results that are not clear to you.
  • Ask him about the course of treatment
  • You can eat anything – there are no specific dietary recommendations for hepatitis B.
  • Whenever possible, try to maintain a balanced diet to strengthen the immune system and improve your well-being.
  • It is recommended to monitor the weight
  • If you already have severe liver damage, your doctor will advise you on diet and advise you to seek the advice of a dietitian.
  • Avoid drinking alcohol as it puts additional strain on your liver.
  • Smoking cessation recommended: Smoking reduces the ability of the immune system to fight the hepatitis virus. When combined with hepatitis B infection, smoking increases the risk of liver cancer.
  • Exercising at the right level of activity improves your health and helps you maintain a healthy weight.
  • Live mindfully: make sure you have enough time to sleep and rest.
  • To better deal with stress, it may be worth learning relaxation techniques such as meditation and yoga.
  • Choose a quiet moment for the daily single dose of pills in your daily routine
  • Store Baraclude in an easily accessible place that is part of your daily routine, such as near a coffee maker or next to toothpaste.
  • Set your alarm clock, mobile phone or smartphone to a regular reminder to take the drug.
  • The hepatitis B virus is transmitted primarily through blood, since it contains the highest concentration of the virus.
  • The virus may be present in other body fluids such as semen, vaginal fluid, or saliva.
  • Do not share hygiene items, such as a toothbrush or straight razor with other people in your household
  • The risk of infection may vary, for example, depending on the viral load.
  • If you are pregnant, you have the opportunity to protect your baby from infection. Your baby may be vaccinated against hepatitis B at birth. Your doctor will tell you more about this.
  • Convince your next of kin to get tested by a doctor for hepatitis B infection and get vaccinated if necessary.
  • You can discuss questions and concerns about you, for example, related to your illness or treatment, during a visit to the doctor for the purpose of examination.
  • Before this visit, write down the questions you would like to ask. At home, you can keep a patient diary as a reminder.
  • Talk with your doctor about test results that are not clear to you.
  • Ask him about the course of treatment

LIFE WITH HEPATITIS B

Although there is still no cure for chronic hepatitis B in most cases, antiviral therapy with drugs such as Baraclude can reduce virus levels to very low levels.Sequential reduction of viral load on the body improves the quality of life and prognosis of the disease, while increasing the chances of avoiding such long-term liver damage as decompensated cirrhosis and cancer.

ADVICE ON DAILY LIVING WITH HEPATITIS B

Nutrition for hepatitis B.

• You can eat anything – there are no specific dietary recommendations for hepatitis B.
• Whenever possible, try to maintain a balanced diet to strengthen the immune system and improve your well-being.
• It is recommended to monitor the weight
• If you already have severe liver damage, your doctor will advise you on diet and advise you to seek the advice of a dietitian.

Alcohol, smoking and hepatitis B

• Avoid drinking alcohol as it puts additional strain on your liver.
• Smoking cessation recommended: Smoking reduces the ability of the immune system to fight the hepatitis virus.When combined with hepatitis B infection, smoking increases the risk of liver cancer.

What else will benefit.

• Exercising at the right level of activity improves your health and helps you maintain a healthy weight.
• Live mindfully: make sure you have enough time to sleep and rest.
• To better deal with stress, it may be worth learning relaxation techniques such as meditation and yoga.

Hepatitis B and travel.

During treatment with Baraclude, there is no reason to not travel as long as you follow these guidelines:

– You must bring a sufficient number of Baraclude

tablets

– Take Baraclude regularly at regular times of admission, including when traveling or on vacation

Inclusion of therapy in the daily routine.

• Choose a quiet moment for the daily single dose of pills in your daily routine
• Store Baraclude in an easily accessible place that is part of your daily routine, such as near a coffee maker or next to toothpaste.
• Set your alarm clock, mobile phone or smartphone to a regular reminder to take the drug.

Prevention of the risk of infection.

• The hepatitis B virus is transmitted primarily through blood, since it contains the highest concentration of the virus.

Therefore, all cuts, scrapes and other bleeding wounds must be kept clean and covered with a waterproof plaster.

• The virus can be present in other body fluids such as semen, vaginal fluid, or saliva.
• Do not share hygiene items, such as a toothbrush or straight razor with other people in your household
• The risk of infection may vary, for example, depending on the viral load.
• If you are pregnant, you have the opportunity to protect your baby from infection. Your baby may be vaccinated against hepatitis B at birth. Your doctor will tell you more about this.
• Convince your next of kin to get tested by a doctor for hepatitis B infection and get vaccinated if necessary.

Planning a doctor’s appointment

• You can discuss questions and concerns about you, for example, related to your disease or treatment, during a visit to the doctor for the purpose of examination.