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Hepatotoxicity Safety Change to Label of Viramune (nevirapine)
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Reported by Jules Levin, NATAP
This article reports to you information from the Viramune Product Insert including new information the FDA inserted by the FDA regarding hepatoxicity and the use of Viramune. Also just below is the letter sent by the FDA to Boehringer Ingleheim Pharmaceuticals regarding the changes in the Product Insert.
Excerpts From Viramune Product Insert
Severe and life-threatening hepatotoxicity, and fatal fulminant hepatitis have been reported in patients treated with VIRAMUNE. Hepatic adverse events have been reported to occur more frequently during the first 18 weeks of treatment, but such events may occur at any time during treatment.
In controlled clinical trials, clinical hepatic events regardless of severity occurred in 4.0% (range 2.5% to 11.0%) of patients who received VIRAMUNE and 1.2% of patients in control groups. Transaminase elevations (ALT or AST > 5X ULN) were observed in 8.8% of patients receiving VIRAMUNE and 6.2% of patients in control groups in clinical trials. (See WARNINGS)
Women and patients with higher CD4 counts are at increased risk of these hepatic events.
The most common clinical toxicity of VIRAMUNE is rash. Severe or life-threatening rash occurred in approximately 2% of VIRAMUNE-treated patients, most frequently within the first 6 weeks of therapy. Rashes are usually mild to moderate, maculopapular erythematous cutaneous eruptions, with or without pruritus, located on the trunk, face and extremities. Women tend to be at higher risk for development of VIRAMUNE associated rash.
Approved by the FDA, July 2003
LETTER FROM FDA
Boehringer Ingleheim Pharmaceuticals, Inc.
Attention: Mr. Kevin Dransfield
Associate Director, Regulatory Affairs
900 Ridgebury Rd./P.O. Box 368
Ridgefield,CT 06877-0368
Dear Mr. Dransfield:
Please refer to your supplemental new drug applications dated October 22, 2003, received October 23, 2003, submitted under section 505(b) of the Federal Food, Drug, and Cosmetic Act for VIRAMUNE (nevirapine) Tablets and VIRAMUNE (nevirapine) Suspension.
These “Changes Being Effected” supplemental new drug applications provide for the inclusion of changes in the VIRAMUNE (nevirapine) labels regarding risk factors for hepatic toxicity associated with VIRAMUNE, as follows.
The inclusion of an additional sentence in the last paragraph of the BOXED WARNING section, to read:
--Women and patients with higher CD4 counts are at increased risk of these hepatic events.
A revision of the third paragraph of the WARNINGS: Hepatic Events section, to read:
--Increased AST or ALT levels and/or co-infection with hepatitis B or C at the start of antiretroviral therapy are associated with a greater risk of hepatic adverse events.
--Women appear to have a three fold higher risk than men for rash-associated hepatic events (4.6% versus 1.5%).
--Patients with higher CD4 counts may also be at higher risk for rash-associated hepatic events with VIRAMUNE.
--In a retrospective review, women with CD4 counts >250 cells/mm 3 had a 9 fold higher risk of rash-associated hepatic adverse events compared to women with CD4 counts <250 cells/mm3 (8.4% versus 0.9%).
--An increased risk was observed in men with CD4 counts >400 cells/mm3 (4.5% versus 0.7% for men with CD4 counts <400 cells/mm3).
We completed our review of these supplemental new drug applications. They are approved, effective on the date of this letter, for use as recommended in the final printed labeling (FPL) submitted on October 22, 2003 (Package insert, Patient Package insert.)
If you issue a letter communicating important information about this drug product (i.e., a “Dear Health Care Professional” letter), we request that you submit a copy of the letter to this NDA and a copy to the following address:
MEDWATCH, HFD-410
FDA
5600 Fishers Lane
Signed by
Debra Birnkrant, M.D.
Director
Division of Antiviral Drug Products
Office of Drug Evaluation IV
Center for Drug Evaluation and Research
VIRAMUNE (nevirapine) Excerpts from the Product Insert
Available in any pharmacy by request
It is essential that patients be monitored intensively during the first 18 weeks of therapy with Viramune to detect potentially life-threatening hepatotoxicity or skin reactions. The greatest risk of severe rash or hepatic events associated with rash occurs in the first six weeks of therapy. However, the risk of any hepatic event, with or without rash, continues past this period and monitoring should continue at frequent intervals.
Increased AST or ALT levels and/or co-infection with hepatitis B or C at the start of antiretroviral therapy are associated with a greater risk of hepatic adverse events. It appears that women and patients with higher CD4 counts (>250 cells/mm3 in women and >400 cells/mm3 in men) may be at higher risk for rash-associated hepatic events with Viramune.
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.
Pharmackinetics in special populations:
Hepatic Impairment: HIV seronegative adults with mild (Child-Pugh Class A; n=6) or moderate (Child-Pugh Class B; n=4) hepatic impairment received a single 200 mg dose of nevirapine in a pharmacokinetic study. In the majority of patients with mild or moderate hepatic impairment, no significant changes were seen in the pharmacokinetics of nevirapine. However, a significant increase in the AUC of nevirapine observed in one patient with Child-Pugh Class B and ascites suggests that patients with worsening hepatic function and ascites may be at risk of accumulating nevirapine in the systemic circulation. Because nevirapine induces its own metabolism with multiple dosing, a single dose study may not reflect the impact of hepatic impairment on multiple dose pharmacokinetics. (See PRECAUTIONS) Nevirapine should not be administered to patients with severe hepatic impairment. (See WARNINGS).
Gender: In one Phase I study in healthy volunteers (15 females, 15 males), the weight-adjusted apparent volume of distribution (Vdss/F) of nevirapine was higher in the female subjects (1.54 L/kg) compared to the males (1.38 L/kg), suggesting that nevirapine was distributed more extensively in the female subjects. However, this difference was offset by a slightly shorter terminal-phase half-life in the females resulting in no significant gender difference in nevirapine oral clearance (24.6±7.7 mL/kg/hr in females vs. 19.9±3.9 mL/kg/hr in males after single dose) or plasma concentrations following either single- or multiple-dose administration(s).
WARNINGS
General:
The first 18 weeks of therapy with VIRAMUNE are a critical period during which intensive monitoring of patients is required to detect potentially life threatening 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.
Resistant virus emerges rapidly and uniformly when VIRAMUNE is administered as monotherapy. Therefore, VIRAMUNE should always be administered in combination with other antiretroviral agents for the treatment of HIV-1 infection.
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 clinical trials,
the risk of 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. These events have progressed to hepatic failure with
transaminase elevation, with or without hyperbilirubinemia, prolonged partial thromboplastin time, or eosinophilia. Rash and fever accompanied some of these hepatic events. Patients with signs or symptoms of hepatitis must immediately seek medical evaluation, have liver function tests performed, and be advised to
discontinue VIRAMUNE as soon as possible.
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. Increased AST or ALT levels and/or co-infection with hepatitis B or C at the start of antiretroviral therapy are associated with a greater risk of hepatic adverse events. It appears that women and patients with higher CD4 counts (>250 cells/mm3 in women and >400 cells/mm3 in men) may be at higher risk for rash-associated hepatic events with VIRAMUNE.
VIRAMUNE should not be administered to patients with severe hepatic impairment. (See CLINICAL PHARMACOLOGY, Pharmacokinetics in Special Populations: Hepatic Impairment; PRECAUTIONS, General).
Intensive clinical and laboratory monitoring, including liver function tests, is essential at baseline and during the first 18 weeks of treatment. (See WARNINGS, General) Monitoring should continue at frequent intervals thereafter, depending on the patient’s clinical status. Liver function tests should be performed if a patient experiences signs or symptoms suggestive of hepatitis and/or hypersensitivity reaction. 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; ADVERSE REACTIONS; DOSAGE AND ADMINISTRATION).
If clinical hepatitis occurs, VIRAMUNE should be permanently discontinued and not restarted after recovery.
Skin Reactions:
Severe, life-threatening skin reactions, including fatal cases, have been reported with VIRAMUNE treatment, 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. 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;
ADVERSE REACTIONS) VIRAMUNE should not be restarted following severe skin rash or hypersensitivity reaction. Some of the risk factors for developing serious cutaneous reactions include failure to follow the initial dosing of 200 mg daily during the 14-day lead-in period and delay in stopping the VIRAMUNE treatment after the onset of the initial symptoms.
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.
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.
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.
Information for Patients:
Patients should be informed of the possibility of severe liver disease or skin reactions associated with VIRAMUNE that may result in death. Patients developing signs or symptoms of liver disease or skin reactions should be instructed to seek medical attention immediately, including performance of laboratory monitoring. Symptoms of liver disease include fatigue, malaise, anorexia, nausea, jaundice, acholic stools, liver tenderness or hepatomegaly. Symptoms of severe skin or hypersensitivity reactions include rash accompanied by fever, general malaise, fatigue, muscle or joint aches, blisters, oral lesions, conjunctivitis, facial edema and/or hepatitis.
Intensive clinical and laboratory monitoring, including liver function tests, is essential during the first 18 weeks of therapy with VIRAMUNE to detect potentially life-threatening hepatotoxicity. However, liver disease can occur
after this period, therefore monitoring should continue at frequent intervals throughout VIRAMUNE treatment. Patients with signs and symptoms of hepatitis should seek medical evaluation immediately. If VIRAMUNE is discontinued due to hepatitis, it should not be restarted. Patients should be advised that co-infection with hepatitis B or C and/or increased liver function tests at the start of antiretroviral therapy are associated with a greater risk of hepatic events with VIRAMUNE. Women and patients with increased CD4+ cell count (>250 cells/mm3 in women and >400 cells/mm3 in men) may be at higher risk for development of rash-associated hepatic events with VIRAMUNE.
The majority of rashes associated with VIRAMUNE occur within the first 6 weeks of initiation of therapy. Patients should be instructed that if any rash occurs during the two-week lead-in period, the VIRAMUNE dose should not be escalated until the rash resolves. Any patient experiencing severe rash or hypersensitivity reactions should discontinue VIRAMUNE and consult a physician. VIRAMUNE should not be restarted following severe skin rash or hypersensitivity reaction. Women tend to be at higher risk for development of VIRAMUNE associated rash.
ADVERSE REACTIONS
Adults:
Clinical practice has shown that the most serious adverse reactions associated with VIRAMUNE are clinical hepatitis/hepatic failure, Stevens-Johnson syndrome, toxic epidermal necrolysis, and hypersensitivity reactions. Clinical hepatitis/hepatic failure may be isolated or associated with signs of hypersensitivity which may include 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.
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