Drugs & Medications News Update New Nevirapine Label Change

New Nevirapine Label Change
Jules Levin
January 13, 2005
NATAP - www.natap.org

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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Last Updated October 12, 2005