New Drugs: Entecavir, Ibandronate Sodium, and Pegaptanib Sodium

Agent for Hepatitis B Virus Infection Approximately 1.25 million Americans have chronic hepatitis B virus (HBV) infection. Spread via infected blood or body fluids, sexual contact, drug abuse by injection, or perinatally from mother to child, it is characterized by early symptoms such as loss of appetite, fever, aches and pains, and itching. Later symptoms include nausea, vomiting, jaundice, dark brown urine, and right-sided abdominal pain. Many patients experience a worsening of the infection, resulting in cirrhosis of the liver, liver cancer, and death. Although vaccines have been developed to provide immunization against HBV, there has been only partial success in the treatment of chronic HBV infection. The infection cannot be cured and only a limited number of treatment options are available. Interferon alfa-2b (Intron A) was the first drug to be approved for the treatment of chronic HBV infection, but its effectiveness is limited, it must be administered parenterally, and most patients experience adverse events. Lamivudine (Epivir HBV) was initially approved for the treatment of human immunodeficiency virus (HIV) infection/acquired immunodeficiency syndrome (AIDS) and, subsequently, for chronic HBV infection. It is administered orally and is better tolerated than interferon alfa-2b; however, many patients have developed resistance to its use. In 2002, adefovir dipivoxil (Hepsera) was marketed and its anti-HBV activity includes some isolates that are resistant to lamivudine. Entecavir (Baraclude— Bristol-Myers Squibb) has been recently approved for the treatment of chronic HBV infection and represents an important addition to the small group of agents that may be considered for the treatment of this infection. It is a guanosine nucleoside analogue, phosphorylated to its triphosphate form, that has activity against HBV polymerase (reverse transcriptase). Entecavir is specifically indicated for the treatment of chronic HBV infection in adults with evidence of active viral replication and either evidence of persistent elevations in serum aminotransferases (ALT or AST) or histologically active disease. In two of the clinical trials, entecavir or lamivudine was used in nucleoside-treatment-naive patients. Entecavir was determined to be superior to lamivudine on the primary efficacy endpoint of histologic improvement and on the secondary efficacy measures of reduction of viral load and ALT normalization. In a third study, entecavir was evaluated in lamivudine-refractory patients, and many patients experienced improvement with the use of the new agent. Entecavir has also been studied in patients co-infected with HBV and HIV who experienced recurrence of HBV viremia while being treated with a lamivudine-containing highly active antiretroviral treatment (HAART) regimen. Either entecavir or placebo was added to the regimen, and approximately one third of the patients receiving the new drug experienced ALT normalization compared with 8% of those receiving placebo. Unlike lamivudine and adefovir, entecavir does not appear to exhibit activity against HIV. The concurrent use of entecavir with HIV nucleoside reverse transcriptase inhibitors is not likely to reduce the efficacy of any of the antiviral agents. Entecavir was well tolerated by almost all patients in the clinical studies with only headache (4%) and fatigue (3%) being reported by more than 1% of the patients. Approximately 12% of patients experienced elevations in ALT to greater than 5 times the upper limit of normal, although the incidence of this response was lower than in the patients treated with lamivudine and the elevations generally resolved with continued treatment. Lactic acidosis and severe hepatomegaly with steatosis have been infrequently associated with the use of nucleoside analogues (e.g., reverse transcriptase inhibitors indicated for the treatment of HIV infection) and this possibility is the subject of a “black box” warning in the labeling for entecavir. Entecavir is classified in pregnancy category C and should only be used in a pregnant woman if the anticipated benefit outweighs the risk. In these situations health care providers are encouraged to register patients in a pregnancy registry by calling 800-2584263. It is not known whether entecavir is excreted in human milk, and mothers treated with the drug should be instructed not to breast-feed. The effectiveness and safety of entecavir in patients below the age of 16 years have not been established. Following oral administration, peak plasma concentrations of entecavir are attained in approximately 1 hour. Administration of the drug with a high-fat meal may delay absorption and decrease its peak concentration and bioavailability. Accordingly, it is recommended that entecavir be administered on an empty stomach at least 2 hours before or after a meal. Entecavir is metabolized to N E W D R U G S