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Pharmaceutical Approval Update July 2011
Manufacturer: Optimer Pharmaceuticals, Inc., San Diego, Calif.
Indication: Fidaxomicin is used to reduce the development of drug-resistant bacteria. To maintain the effectiveness of fidaxomicin and other antibacterial drugs, fidaxomicin should be used only to treat infections that are caused by Clostridium difficile.
Biological Class: Fidaxomicin is an oral macrolide antibacterial drug. Its chemical name is oxacyclooctadeca-3,5,9,13,15-pentaen-2-one, 3-[[[6-deoxy-4-O-(3,5-dichloro-2-ethyl-4,6-dihydroxybenzoyl)-2-O-methyl-β-D-mannopyranosyl] oxy]methyl]-12-[[6-deoxy-5-C-methyl-4-O-(2-methyl-1-oxopropyl)-β-D-lyxo-hexopyranosyl]oxy]-11-ethyl-8-hydroxy-18-[(1R)-1-hydroxyethyl]-9,13,15-trimethyl-(3E,5E,8S,9E,11S,12R,13E,15E,18S.
Uniqueness of Biologic: Fidaxomicin is the first antibacterial agent indicated for C. difficile–associated diarrhea (CDAD) to be approved in nearly 30 years. Fidaxomicin acts locally in the gastrointestinal (GI) tract on C. difficile.
Warnings and Precautions: Because systemic absorption of fidaxomicin is minimal, this drug is not effective for the treatment of systemic infections.
Prescribing fidaxomicin in the absence of a proven or strongly suspected C. difficile infection is unlikely to benefit patients and increases the risk of the development of drug-resistant bacteria.
Adverse Reactions: The most common adverse reactions are nausea, vomiting, abdominal pain, GI hemorrhage, anemia, and neutropenia.
Dosage and Administration: Fidaxomicin is taken as 200-mg tablets twice daily with or without food.
Use in Specific Populations:
Geriatric patients. Despite greater exposures in elderly patients, plasma levels of fidaxomicin and OP-1118 (the drug’s major metabolite) remained in the nanogram-per-milliliter (ng/mL) range.
Gender. No dose adjustment is recommended based on the patient’s sex.
Renal impairment. No dose adjustment is recommended based on renal function.
Hepatic impairment. The impact of hepatic impairment on the pharmacokinetics of fidaxomicin has not been evaluated. Because the drug and OP-1118 do not appear to undergo significant hepatic metabolism, their elimination is not expected to be significantly affected by hepatic impairment.
Drug Interactions. In controlled trials, fidaxomicin had no significant impact on the pharmacokinetics of the following drugs when administered concomitantly: digoxin (Lanoxin), midazolam (Versed, Roche), warfarin (e.g., Coumadin, Bristol-Myers Squibb/Sanofi-aventis), and omeprazole (Prilosec, AstraZeneca). No dose adjustment is warranted when fidaxomicin is given with substrates of P-glycoprotein or cytochrome P450 (CYP) enzymes.
Commentary: CDAD has become a significant medical problem in hospitals, long-term-care facilities, and the community. This serious illness results from infection of the inner lining of the colon by C. difficile bacteria, which produce toxins that cause inflammation of the colon, severe diarrhea and, in the most serious cases, death. CDAD typically develops from the use of broad-spectrum antibiotics that disrupt normal GI flora, possibly allowing these bacteria to flourish. Older patients are especially at risk for CDAD, possibly because of a weakened immune system or the presence of underlying disease. Approximately two-thirds of CDAD patients are 65 years of age or older.
In two large phase 3 clinical studies, fidaxomicin therapy resulted in a response rate that was non-inferior to that for oral vancomycin (e.g., Vancocin) at the end of the 10-day treatment period. The drug was also superior to vancomycin in sustaining responses for 25 days beyond the end of treatment. Fidaxomicin is the only FDA-approved antibacterial drug that has been shown to be superior to vancomycin in sustained clinical responses for CDAD.
Manufacturer: Tibotec Therapeutics, Division of Centocor Ortho Biotech, Raritan, N.J.
Indication: Rilpivirine is taken once daily in combination with other antiretroviral medications for the treatment of HIV type 1 (HIV-1) infection in adults who have not received previous antiretroviral therapy.
Drug Class: Rilpivirine is a diarylpyrimidine non-nucleoside reverse transcriptase inhibitor (NNRTI) of HIV-1. Each tablet contains 27.5 mg of rilpivirine HCl, which is equivalent to 25 mg of rilpivirine. The chemical name is 4-[[4-[[4-[(E)-2-cyanoethenyl]-2,6-dimethylphenyl]amino]2-pyrimidinyl] amino]benzonitrile monohydrochloride. The molecular weight is 402.88.
Uniqueness of Drug: Rilpivirine blocks HIV-1 replication by noncompetitive inhibition of HIV-1 reverse transcriptase; however, it does not inhibit the human cellular DNA polymerases alpha, beta, or gamma. This medication should be used as part of a highly active antiretroviral therapy (HAART) regimen that is designed to suppress the amount of HIV in the blood.
Warnings and Precautions:
Drug interactions. In healthy subjects, supra-therapeutic doses of rilpivirine (75 mg once daily and 300 mg once daily) can prolong the corrected QT interval of the electrocardiogram. Rilpivirine should be used with caution when coadministered with other drugs that pose a known risk of torsades de pointes.
Depressive disorders. Depressed mood, depression, dysphoria, major depression, altered mood, negative thoughts, suicide attempts, and suicidal ideation have been reported with rilpivirine. Most events were mild or moderate in severity. In a study comparing rilpivirine and efavirenz (Sustiva, Bristol-Myers Squibb), the incidence of grade 3 and 4 depressive disorders, regardless of cause, was 1% for both drugs. The rate of discontinuation of therapy stemming from depressive disorders with either drug was 1% in each arm. Suicide attempts were reported in two rilpivirine patients, and suicide ideation was reported in one rilpivirine patient and in three efavirenz patients. Patients with severe depressive symptoms should seek immediate medical evaluation to establish whether the symptoms are related to rilpivirine; if they are related, it should be determined whether the risks of continued therapy outweigh the benefits.
Fat redistribution. Redistribution or accumulation of body fat, including central obesity, dorsocervical fat enlargement, peripheral or facial wasting, breast enlargement, and cushingoid appearance have been observed with antiretroviral therapy. The mechanism and long-term consequences of these events are currently unknown. A causal relationship has not been established.
Immune reconstitution syndrome. In patients receiving combination antiretroviral therapy, including rilpivirine, the immune reconstitution syndrome has been reported. During the initial phase of combination antiretroviral treatment, patients whose immune system responds to treatment may develop an inflammatory response to indolent or residual opportunistic infections (such as Mycobacterium avium complex, cytomegalovirus, Pneumocystis jiroveci pneumonia, and tuberculosis). Such a response may necessitate further evaluation and treatment.
Commentary: Rilpivirine, a member of the NNRTI class, blocks the ability of HIV-1 to reproduce itself. The tablet is taken once daily with food. The FDA’s approval of this medication provides an additional treatment option for patients who are starting HIV therapy.
In a study comparing rilpivirine and efavirenz, another NNRTI, both drugs resulted in undetectable HIV levels after 48 weeks for about 80% of patients. In its approval announcement, however, the FDA noted that people with high viral loads were less likely to respond to rilpivirine than efavirenz. When therapy failed, patients taking rilpivirine were more likely to develop resistance to the drugs in their regimen compared with patients taking efavirenz.
Although the most common side effects were similar to those experienced with efavirenz (depression, difficulty sleeping, headaches, and rash), patients taking rilpivirine generally had fewer side effects than those receiving efavirenz.
The FDA approved rilpivirine on the basis of data from two phase 3 clinical trials involving 1,368 adults who had not received prior HIV therapy as well as data from an extension trial. Patients received rilpivirine or efavirenz as well as other anti-HIV drugs. In the two trials, 84.3% of rilpivirine patients were able to achieve suppression of the virus to undetectable levels compared with 82.3% of efavirenz patients. Those who started the trials with a high viral load and who received rilpivirine were less likely to respond to therapy than those who received efavirenz. The converse was true for patients who started with a low level of virus. Patients were more likely to drop out because of adverse effects if they were taking efavirenz, leading some observers to call the new medication a trade-off.
Manufacturer: Merck & Co., Whitehouse Station, N.J.
Indication: Boceprevir is a protease inhibitor (PI) that is used for the treatment of patents with chronic hepatitis C virus (HCV) genotype 1 infection. This medication must be given in combination with peginterferon alfa injections and ribavirin tablets (e.g., PegIntron and Rebetol).
Drug Class: Boceprevir is the first in a new class of medications known as HCV PIs approved for use in combination with peginterferon alfa and ribavirin, the current standard therapy for patients with chronic HCV infection.
Uniqueness of Drug: Boceprevir inhibits HCV nonstructural protein 3 (NS3) serine protease. The drug’s chemical name is (1R,5S)-N-[3-amino-1-(cyclobutylmethyl)-2,3-dioxo-propyl]-3-[2(S)-[[[(1,1-methylethyl)amino]carbonyl]amino]-3,3-dimethyl-1-oxobutyl]-6,6-dimethyl-3-azabicyclo [3.1.0] hexan-2(S)-carboxamide. The molecular weight is 519.7.
Warnings and Precautions:
Pregnancy. When boceprevir is used with ribavirin, ribavirin may cause birth defects or death of the exposed fetus. Extreme care must be taken to ensure that pregnancy is avoided in female patients and in the female partners of male patients. Ribavirin should not be started unless a negative pregnancy test result has been obtained immediately before therapy begins. Men and women of childbearing age must use at least two forms of contraception during treatment and for at least six months after the end of treatment. Routine monthly pregnancy tests must be performed during this time. Systemic hormonal contraceptives might not be as effective in women while they are taking boceprevir. Women should use two alternative methods of contraception, including intrauterine devices and barrier methods during therapy with boceprevir and concomitant ribavirin.
Anemia. The addition of boceprevir to peginterferon alfa and ribavirin has been associated with an extra decrease in hemoglobin concentrations. Complete blood counts should be obtained before therapy and at treatment weeks 4, 8, and 12. If the hemoglobin level is less than 10 g/dL, a decrease in dosage or interruption of ribavirin is recommended. If the hemoglobin level is less than 8.5 g/dL, ribavirin should be discontinued. Thromboembolic events have been associated with erythropoiesis-stimulating agents in other diseases and have been reported with the use of peginterferon alfa in patients with HCV infection.
Neutropenia. In phase 2 and 3 clinical trials, 7% of subjects receiving a combination of boceprevir with peginterferon alfa and ribavirin had neutrophil counts of less than 0.5 × 109/liter compared with 4% of subjects receiving peginterferon alfa and ribavirin alone. Decreases in neutrophil counts may require dose reduction or discontinuation of peginterferon alfa and ribavirin.
Laboratory tests. HCV–RNA levels should be monitored at treatment weeks 4, 8, 12, and 24; at the end of treatment; during follow-up; and at other time points as indicated. The use of a sensitive real-time–reverse-transcription polymerase chain reaction assay for monitoring HCV–RNA levels during treatment is recommended.
Dosage and Administration: Boceprevir is available as 200-mg hard gelatin capsules for oral administration. The dose is 800 mg (four 200-mg capsules) three times daily every seven to nine hours with a meal or a light snack.
Adverse Drug Reactions: In clinical trials of boceprevir plus peginterferon alfa and ribavirin, adult patients commonly reported fatigue, anemia, nausea, headache, and taste distortion. Boceprevir is also associated with some manageable and reversible hematological adverse effects, including anemia, neutropenia, and thrombocytopenia.
Commentary: HCV infection, a liver disease, is spread when the blood of an infected person enters the blood of another person, such as may occur through shared needles or other nonsterile instruments (e.g., body piercings and tattoos). About 3.2 million Americans have HCV infection.
In two studies, boceprevir, when used in combination with other drugs, was far more effective in treating hepatitis C. However, some groups of individuals, such as African-Americans and patients with more advanced disease, did not respond well to boceprevir. A small number of patients (fewer than 1%) also reported suicidal and homicidal ideation.
Boceprevir offers a greater chance of cure for some patients compared with other available therapies. In Merck’s clinical trials, boceprevir yielded sustained virological response rates as high as 67% in patients with difficult-to-treat HCV genotype 1. By contrast, the rate for patients receiving the standard regimen of peginterferon alfa injections and ribavirin tablets was about 40%. Until now, treatment relied on boosting the immune system rather than attacking the virus directly.