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FDA Public Health Advisory for Nevirapine (Viramune)
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I sent out a notice about this last week & today the FDA issued this notice. The report I issued last week follows below the FDA announcement. Jules Levin
The Food and Drug Administration (FDA) is issuing a public health advisory to inform health care providers and patients about recent safety-related changes to the nevirapine (Viramune) label (package insert) and about appropriate use of HIV triple combination therapy containing nevirapine, which is one treatment option in the United States and which is increasingly being used globally. The nevirapine label has been revised several times over the last two years to include more information on liver toxicity associated with long term nevirapine use. The Indications and Usage section of the Viramune label now recommends against starting nevirapine treatment in women with CD4+cell counts greater than 250 cells/mm3 unless benefits clearly outweigh risks. This recommendation is based on a higher observed risk of serious liver toxicity in patients with higher CD4 cell counts prior to initiation of therapy. In addition, the revised label now includes a Medication Guide to inform patients about risks associated with nevirapine when used for the treatment of HIV.
Both clinically symptomatic and asymptomatic liver toxicity are observed with long term use of nevirapine in combination with other HIV drugs. Asymptomatic liver toxicity is defined as increases in liver enzymes without any associated clinical signs or symptoms and is similar to that seen with other antiretroviral drugs. Symptomatic liver toxicity is more common with nevirapine compared to other antiretroviral drugs. Important information regarding symptomatic nevirapine liver toxicity is summarized below:
* Symptomatic nevirapine liver toxicity consists of elevated liver enzymes plus at least one symptom, which is typically rash but may include flu-like symptoms or fever. The severity of symptomatic liver toxicity ranges from mild symptoms with liver enzyme abnormalities to rapidly occurring liver failure and death.
* Symptomatic nevirapine liver toxicity typically occurs after only a few weeks of dosing and may progress to liver failure despite monitoring of laboratory tests, which is not characteristic of other antiretrovirals.
* Females and patients with higher CD4+ cell counts are at increased risk of liver toxicity. Females have a three fold higher risk of symptomatic nevirapine liver toxicity than males, and females with CD4+ cell counts > 250 cells/mm3 have a 12 fold higher risk of symptomatic liver toxicity than females with CD4+ cell counts < 250 (11% vs. 0.9%). Males with CD4+ cell counts > 400 cells/mm3 have a three fold higher risk of symptomatic liver toxicity than males with CD4+ cell counts < 400 (6.3% vs. 2.3%).
* Nevirapine-related deaths due to symptomatic liver toxicity, including some in HIV-infected pregnant women, have been reported to FDA's Medwatch program. Serious and fatal liver toxicity has not been reported after single doses of nevirapine.
In spite of the potential for serious and life-threatening liver toxicity and skin rashes with nevirapine, there are multiple reasons why nevirapine remains an important part of an HIV treatment regimen for many HIV-infected individuals world-wide. These reasons include:
* Triple antiretroviral regimens have been shown to have a large impact on the reduction of AIDS morbidity and mortality. Triple antiretroviral drug regimens containing a protease inhibitor (PI) or a non-nucleoside reverse transcriptase inhibitor (NNRTI), such as nevirapine, are standard of care for HIV treatment and are needed to adequately and durably suppress virus.
* Many options are needed for HIV-infected patients since resistance to antiretroviral drugs or to an entire antiretroviral class can develop.
* Symptomatic liver toxicity has not been reported with the use of single doses of nevirapine to the mother and to the child for prevention of perinatal HIV infection.
* Alternatives to nevirapine are limited by other toxicities, potential drug interactions, and by the risk of drug related birth defects if given to a female in the first trimester of pregnancy.
* Nevirapine liver toxicity is less frequent (<2% for both males and females with CD4+ cell counts <250 cells/mm3) when started in patients with lower CD4 counts. Therefore, symptomatic liver toxicity in resource poor countries is likely to be much lower if World Health Organization standards are used for starting treatment. The WHO recommends the initiation of ART treatment in patients with advanced disease or with CD4 counts < 200 cells/mm3.
* Nevirapine is chemically stable in environmental conditions where other antiretrovirals are not.
* Symptomatic liver toxicity has not been reported in HIV-infected children, and nevirapine is available in a liquid formulation while many other antiretrovirals are not.
In conclusion, the seriousness of the underlying disease must be considered as part of the risk benefit analysis when treating HIV-infected patients. HIV infection will progress to AIDS and death if untreated. Treatment with combination antiretroviral drugs, including nevirapine, can slow clinical progression and may delay the development of AIDS or death for years. Health care providers should weigh the benefits and risks associated with nevirapine use before prescribing nevirapine for the treatment of their HIV-infected patients.
Richard Klein
Office of Special Health Issues
Food and Drug Administration
Jeffrey Murray
Division of Antiviral Drug Products
Food and Drug Administration
New Nevirapine Label Change
Jules Levin
January 13, 2005
It was announced that there will be new language in the label of Viramune regarding hepatoxocity. Also starting now when you buy nevirapine at the pharmacy you are supposed to receive a 3-page Medication Guide, as you do when you buy Ziagen which warns about hypersensitivity. This Medication Guide is for patients and explains the liver concerns discussed below.
NEW FDA LABEL FOR VIRAMUNE (nevirapine); this language is newly put into the Viramune Package insert on page 8:
"Based on serious and life-threatening hepatotoxicity observed in controlled and uncontrolled studies, VIRAMUNE should not be initiated in adult females with CD4+ cell counts greater than 250 cells/mm3 or in adult males with CD4+ cell counts greater than 400 cells/mm3 unless the benefit outweighs the risk (see WARNINGS)."
This information is NOT new. It's about a year ago that Boehringer-Ingelheim & the FDA warned that there is a potential for hepatoxicity for women starting Viramune with over 250 CD4s and men with over 400 CD4s, but the FDA & Boerhinger now agreed to put out this new language in the Viramune label.
Although it's not in the label if you stop or interrupt Viramune if you are considering restarting the drug you should abide by these same rules to be safe.
WARNINGS
HERE IS THE LANGUAGE FROM THE WARNING SECTION RELEVANT TO THE LABEL ABOVE:
The patients at greatest risk of hepatic events, including potentially fatal events, are women with high CD4 counts. In general, during the first 6 weeks of treatment, women have a three fold higher risk than men for symptomatic, often rash-associated, hepatic events (5.8% versus 2.2%), and patients with higher CD4 counts at initiation of VIRAMUNE therapy are at higher risk for symptomatic hepatic events with VIRAMUNE. In a retrospective review, women with CD4 counts >250 cells/mm3 had a 12 fold higher risk of symptomatic hepatic adverse events compared to women with CD4 counts <250 cells/mm3 (11.0% versus 0.9%). An increased risk was observed in men with CD4 counts >400 cells/mm3 (6.3% versus 1.2% for men with CD4 counts <400 cells/mm3). However, all patients, regardless of gender, CD4 count, or antiretroviral treatment history, should be monitored for hepatotoxicity since symptomatic hepatic adverse events have been reported at all CD4 counts. Co-infection with hepatitis B or C and/or increased liver function tests at the start of therapy with VIRAMUNE are associated with a greater risk of later symptomatic events (6 weeks or more after starting VIRAMUNE) and asymptomatic increases in AST or ALT.
In addition, serious hepatotoxicity (including liver failure requiring transplantation in one instance) has been reported in HIV -uninfected individuals receiving multiple doses of VIRAMUNE in the setting of post-exposure prophylaxis, an unapproved use.
Because increased nevirapine levels and nevirapine accumulation may be observed in patients with serious liver disease, VIRAMUNE should not be administered to patients with severe hepatic impairment (see CLINICAL PHARMACOLOGY, Pharmacokinetics in Special Populations: Hepatic Impairment; PRECAUTIONS, General).
THE REMAINDER OF THE WARNING SECTION READS:
WARNINGS
General:
The most serious adverse reactions associated with VIRAMUNE (nevirapine) are hepatitis/hepatic failure, Stevens -Johnson syndrome, toxic epidermal necrolysis, and hypersensitivity reactions. Hepatitis/hepatic failure may be associated with signs of hypersensitivity which can include severe rash or rash accompanied by fever, general malaise, fatigue, muscle or joint aches, blisters, oral lesions, conjunctivitis, facial edema, eosinophilia, granulocytopenia, lymphadenopathy, or renal dysfunction.
The first 18 weeks of therapy with VIRAMUNE are a critical period during which intensive clinical and laboratory monitoring of patients is required to detect potentially lifethreatening hepatic events and skin reactions. The optimal frequency of monitoring during this time period has not been established. Some experts recommend clinical and laboratory monitoring more often than once per month, and in particular, would include monitoring of liver function tests at baseline, prior to dose escalation and at two weeks post-dose escalation. After the initial 18 week period, frequent clinical and laboratory monitoring should continue throughout VIRAMUNE treatment. In addition, the 14-day lead-in period with VIRAMUNE 200 mg daily dosing has been demonstrated to reduce the frequency of rash.
Hepatic Events:
Severe, life-threatening, and in some cases fatal hepatotoxicity, including fulminant and cholestatic hepatitis, hepatic necrosis and hepatic failure, have been reported in patients treated with VIRAMUNE. In controlled clinical trials, symptomatic hepatic events regardless of severity occurred in 4% (range 0% to 11.0%) of patients who received VIRAMUNE and 1.2% of patients in control groups.
The risk of symptomatic hepatic events regardless of severity was greatest in the first 6 weeks of therapy. The risk continued to be greater in the VIRAMUNE groups compared to controls through 18 weeks of treatment. However, hepatic events may occur at any time during treatment. In some cases, patients presented with non-specific, prodromal signs or symptoms of fatigue, malaise, anorexia, nausea, jaundice, liver tenderness or hepatomegaly, with or without initially abnormal serum transaminase levels. Rash was observed in approximately half of the patients with symptomatic hepatic adverse events. Fever and flu-like symptoms accompanied some of these hepatic events. Some events, particularly those with rash and other symptoms, have progressed to hepatic failure with transaminase elevation, with or without hyperbilirubinemia, hepatic encephalopathy, prolonged partial thromboplastin time, or eosinophilia. Patients with signs or symptoms of hepatitis must be advised to discontinue VIRAMUNE and immediately seek medical evaluation, which should include liver function tests.
Liver function tests should be performed immediately if a patient experiences signs or symptoms suggestive of hepatitis and/or hypersensitivity reaction. Liver function tests should also be obtained immediately for all patients who develop a rash in the first 18 weeks of treatment. Physicians and patients should be vigilant for the appearance of signs or symptoms of hepatitis, such as fatigue, malaise, anorexia, nausea, jaundice, bilirubinuria, acholic stools, liver tenderness or hepatomegaly. The diagnosis of hepatotoxicity should be considered in this setting, even if liver function tests are initially normal or alternative diagnoses are possible (see PRECAUTIONS, Information for Patients; DOSAGE AND ADMINISTRATION).
If clinical hepatitis or transaminase elevations combined with rash or other systemic symptoms occur, VIRAMUNE should be permanently discontinued. Do not restart VIRAMUNE after recovery. In some cases, hepatic injury progresses despite discontinuation of treatment. The patients at greatest risk of hepatic events, including potentially fatal events, are women with high CD4 counts. In general, during the first 6 weeks of treatment, women have a three fold higher risk than men for symptomatic, often rash-associated, hepatic events (5.8% versus 2.2%), and patients with higher CD4 counts at initiation of VIRAMUNE therapy are at higher risk for symptomatic hepatic events with VIRAMUNE. In a retrospective review, women with CD4 counts >250 cells/mm3 had a 12 fold higher risk of symptomatic hepatic adverse events compared to women with CD4 counts <250 cells/mm3 (11.0% versus 0.9%). An increased risk was observed in men with CD4 counts >400 cells/mm3 (6.3% versus 1.2% for men with CD4 counts <400 cells/mm3). However, all patients, regardless of gender, CD4 count, or antiretroviral treatment history, should be monitored for hepatotoxicity since symptomatic hepatic adverse events have been reported at all CD4 counts. Co-infection with hepatitis B or C and/or increased liver function tests at the start of therapy with VIRAMUNE® are associated with a greater risk of later symptomatic events (6 weeks or more after starting VIRAMUNE) and asymptomatic increases in AST or ALT.
In addition, serious hepatotoxicity (including liver failure requiring transplantation in one instance) has been reported in HIV -uninfected individuals receiving multiple doses of VIRAMUNE in the setting of post-exposure prophylaxis, an unapproved use.
Because increased nevirapine levels and nevirapine accumulation may be observed in patients with serious liver disease, VIRAMUNE should not be administered to patients with severe hepatic impairment (see CLINICAL PHARMACOLOGY, Pharmacokinetics in Special Populations: Hepatic Impairment; PRECAUTIONS, General).
Skin Reactions:
Severe and life-threatening skin reactions, including fatal cases, have been reported, occurring most frequently during the first 6 weeks of therapy. These have included cases of Stevens- Johnson syndrome, toxic epidermal necrolysis, and hypersensitivity reactions characterized by rash, constitutional findings, and organ dysfunction including hepatic failure. In controlled clinical trials, Grade 3 and 4 rashes were reported during the first 6 weeks in 1.5% of VIRAMUNE recipients compared to 0.1% of placebo subjects.
Patients developing signs or symptoms of severe skin reactions or hypersensitivity reactions (including, but not limited to, severe rash or rash accompanied by fever, general malaise, fatigue, muscle or joint aches, blisters, oral lesions, conjunctivitis, facial edema, and/or hepatitis, eosinophilia, granulocytopenia, lymphadenopathy, and renal dysfunction) must permanently discontinue VIRAMUNE and seek medical evaluation immediately (see PRECAUTIONS, Information for Patients). Do not restart VIRAMUNE following severe skin rash, skin rash combined with increased transaminases or other symptoms, or hypersensitivity reaction. If patients present with a suspected VIRAMUNE -associated rash, liver function tests should be performed. Patients with rash-associated AST or ALT elevations should be permanently discontinued from VIRAMUNE.
Therapy with VIRAMUNE must be initiated with a 14-day lead-in period of 200 mg/day (4 mg/kg/day in pediatric patients), which has been shown to reduce the frequency of rash. If rash is observed during this lead-in period, dose escalation should not occur until the rash has resolved (see DOSAGE AND ADMINISTRATION). Patients should be monitored closely if isolated rash of any severity occurs. Delay in stopping VIRAMUNE treatment after the onset of rash may result in a more serious reaction.
Women appear to be at higher risk than men of developing rash with VIRAMUNE. In a clinical trial, concomitant prednisone use (40 mg/day for the first 14 days of VIRAMUNE administration) was associated with an increase in incidence and severity of rash during the first 6 weeks of VIRAMUNE therapy. Therefore, use of prednisone to prevent VIRAMUNE-associated rash is not recommended.
Resistance
VIRAMUNE must not be used as a single agent to treat HIV or added on as a sole agent to a failing regimen. As with all other non-nucleoside reverse transcriptase inhibitors, resistant virus emerges rapidly when nevirapine is administered as monotherapy. The choice of new antiretroviral agents to be used in combination with nevirapine should take into consideration the potential for cross resistance. When discontinuing an antiretroviral regimen containing VIRAMUNE, the long half-life of nevirapine should be taken into account; if antiretrovirals with shorter half-lives than VIRAMUNE are stopped concurrently, low plasma concentrations of nevirapine alone may persist for a week or longer and virus resistance may subsequently develop.
St. John's wort:
Concomitant use of St. John's wort (hypericum perforatum) or St. John's wort containing products and VIRAMUNE is not recommended. Co-administration of non-nucleoside reverse transcriptase inhibitors (NNRTIs), including VIRAMUNE, with St. John's wort is expected to substantially decrease NNRTI concentrations and may result in sub-optimal levels of VIRAMUNE and lead to loss of virologic response and possible resistance to VIRAMUNE or to the class of NNRTIs.
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