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The most serious adverse reactions associated with VIRAMUNE 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 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, include monitoring of liver enzyme 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 [see DOSAGE AND ADMINISTRATION].
Hepatotoxicity And Hepatic Impairment
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%) of subjects who received VIRAMUNE and 1% of subjects 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, subjects presented with nonspecific, 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 subjects 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. Rhabdomyolysis has been observed in some patients experiencing skin and/or liver reactions associated with VIRAMUNE use. Patients with signs or symptoms of hepatitis must be advised to discontinue VIRAMUNE and immediately seek medical evaluation, which should include liver enzyme tests.
Transaminases should be checked immediately if a patient experiences signs or symptoms suggestive of hepatitis and/or hypersensitivity reaction. Transaminases should also be checked 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 transaminases are initially normal or alternative diagnoses are possible [see BOXED WARNING and DOSAGE AND ADMINISTRATION].
If clinical hepatitis or transaminase elevations combined with rash or other systemic symptoms occur, permanently discontinue VIRAMUNE. 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+ cell counts. In general, during the first 6 weeks of treatment, women have a 3-fold higher risk than men for symptomatic, often rash-associated, hepatic events (6% versus 2%), and patients with higher CD4+ cell counts at initiation of VIRAMUNE therapy are at higher risk for symptomatic hepatic events with VIRAMUNE. In a retrospective review, women with CD4+ cell counts greater than 250 cells/mm³ had a 12-fold higher risk of symptomatic hepatic adverse events compared to women with CD4+ cell counts less than 250 cells/mm³ (11% versus 1%). An increased risk was observed in men with CD4+ cell counts greater than 400 cells/mm³ (6% versus 1% for men with CD4+ cell counts less than 400 cells/mm³ ). However, all patients, regardless of gender, CD4+ cell count, or antiretroviral treatment history, should be monitored for hepatotoxicity since symptomatic hepatic adverse events have been reported at all CD4+ cell counts. Co-infection with hepatitis B or C and/or increased transaminase elevations 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-1 uninfected individuals receiving multiple doses of VIRAMUNE in the setting of post-exposure prophylaxis (PEP), an unapproved use. Use of VIRAMUNE for occupational and non-occupational PEP is contraindicated [see CONTRAINDICATIONS].
Increased nevirapine trough concentrations have been observed in some patients with hepatic fibrosis or cirrhosis. Therefore, carefully monitor patients with either hepatic fibrosis or cirrhosis for evidence of drug-induced toxicity. Do not administer nevirapine to patients with moderate or severe (Child-Pugh Class B or C, respectively) hepatic impairment [see CONTRAINDICATIONS, Use In Specific Populations, and CLINICAL PHARMACOLOGY].
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. Rhabdomyolysis has been observed in some patients experiencing skin and/or liver reactions associated with VIRAMUNE use. In controlled clinical trials, Grade 3 and 4 rashes were reported during the first 6 weeks in 2% of VIRAMUNE recipients compared to less than 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 BOXED WARNING]. 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, measure transaminases immediately. Permanently discontinue VIRAMUNE in patients with rash-associated transaminase elevations.
Therapy with VIRAMUNE must be initiated with a 14-day lead-in period of 200 mg per day (150 mg/m² per day in pediatric patients), which has been shown to reduce the frequency of rash. Discontinue VIRAMUNE if a patient experiences severe rash or any rash accompanied by constitutional findings. Do not increase VIRAMUNE dose to a patient experiencing a mild to moderate rash without constitutional symptoms during the 14-day lead-in period of 200 mg per day (150 mg/m²/day in pediatric patients) until the rash has resolved. The total duration of the once-daily lead-in dosing period must not exceed 28 days at which point an alternative regimen should be sought [see DOSAGE AND ADMINISTRATION Patients must 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 per 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.
VIRAMUNE must not be used as a single agent to treat HIV-1 or added on as a sole agent to a failing regimen. 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 [see Microbiology].
See Table 4 for listings of established and potential drug interactions [see DRUG INTERACTIONS].
Concomitant use of St. John's wort (Hypericum perforatum) or St. John's wort-containing products and VIRAMUNE is not recommended. Co-administration of St. John's wort with non-nucleoside reverse transcriptase inhibitors (NNRTIs), including VIRAMUNE, 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. Coadministration of VIRAMUNE and efavirenz is not recommended as this combination has been associated with an increase in adverse reactions and no improvement in efficacy.
Immune Reconstitution Syndrome
Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including VIRAMUNE. During the initial phase of combination antiretroviral treatment, patients whose immune system responds may develop an inflammatory response to indolent or residual opportunistic infections (such as Mycobacterium avium infection, cytomegalovirus, Pneumocystis jiroveci pneumonia, or tuberculosis), which may necessitate further evaluation and treatment.
Autoimmune disorders (such as Graves' disease, polymyositis, and Guillain-Barré syndrome) have also been reported to occur in the setting of immune reconstitution, however, the time to onset is more variable, and can occur many months after initiation of treatment.
Redistribution/accumulation of body fat including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and “cushingoid appearance” have been observed in patients receiving antiretroviral therapy. The mechanism and long-term consequences of these events are currently unknown. A causal relationship has not been established.
Patient Counseling Information
Advise the patient to read the FDA-approved patient labeling (Medication Guide).
- Hepatotoxicity and Skin Reactions
Inform patients of the possibility of severe liver disease or skin reactions associated with VIRAMUNE that may result in death. Instruct patients developing signs or symptoms of liver disease or severe skin reactions to discontinue VIRAMUNE and 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 enzymes, is essential during the first 18 weeks of therapy with VIRAMUNE to detect potentially life-threatening hepatotoxicity and skin reactions. However, liver disease can occur after this period; therefore, monitoring should continue at frequent intervals throughout VIRAMUNE treatment. Extra vigilance is warranted during the first 6 weeks of therapy, which is the period of greatest risk of hepatic events and skin reactions. Advise patients with signs and symptoms of hepatitis to discontinue VIRAMUNE and seek medical evaluation immediately. If VIRAMUNE is discontinued due to hepatotoxicity, do not restart it. Patients, particularly women, with increased CD4+ cell count at initiation of VIRAMUNE therapy (greater than 250 cells/mm³ in women and greater than 400 cells/mm³ in men) are at substantially higher risk for development of symptomatic hepatic events, often associated with rash. Advise patients that co-infection with hepatitis B or C and/or increased transaminases 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 [see BOXED WARNING and WARNINGS AND PRECAUTIONS].
The majority of rashes associated with VIRAMUNE occur within the first 6 weeks of initiation of therapy. Instruct patients that if any rash occurs during the two-week lead-in period, do not escalate the VIRAMUNE dose until the rash resolves. The total duration of the once-daily lead-in dosing period should not exceed 28 days, at which point an alternative regimen may need to be started. Any patient experiencing a rash should have their liver enzymes (AST, ALT) evaluated immediately. Patients with severe rash or hypersensitivity reactions should discontinue VIRAMUNE immediately 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 [see BOXED WARNING and WARNINGS AND PRECAUTIONS].
Inform patients to take VIRAMUNE every day as prescribed. Patients should not alter the dose without consulting their doctor. If a dose is missed, patients should take the next dose as soon as possible. However, if a dose is skipped, the patient should not double the next dose. Advise patients to report to their doctor the use of any other medications.
VIRAMUNE is not a cure for HIV-1 infection; patients may continue to experience illnesses associated with advanced HIV-1 infection, including opportunistic infections. Advise patients to remain under the care of a physician when using VIRAMUNE.
Patients should be told that sustained decreases in plasma HIV RNA have been associated with a reduced risk of progression to AIDS and death.
Advise patients to avoid doing things that can spread HIV-1 infection to others.
- Do not share needles or other injection equipment.
- Do not share personal items that can have blood or body fluids on them, like toothbrushes and razor blades.
- Do not have any kind of sex without protection. Always practice safe sex by using a latex or polyurethane condom to lower the chance of sexual contact with semen, vaginal secretions, or blood.
- Do not breastfeed. We do not know if VIRAMUNE can be passed to your baby in your breast milk and whether it could harm your baby. Also, mothers with HIV-1 should not breastfeed because HIV-1 can be passed to the baby in the breast milk.
Inform patients that they should not take VIRAMUNE tablets or oral suspension and VIRAMUNE XR extended release tablets at the same time.
- Drug Interactions
VIRAMUNE may interact with some drugs; therefore, patients should be advised to report to their doctor the use of any other prescription, non-prescription medication or herbal products, particularly St. John's wort [see WARNINGS AND PRECAUTIONS and DRUG INTERACTIONS].
Hormonal methods of birth control, other than depomedroxy-progesterone acetate (DMPA), should not be used as the sole method of contraception in women taking VIRAMUNE, since VIRAMUNE may lower the plasma levels of these medications. Additionally, when oral contraceptives are used for hormonal regulation during VIRAMUNE therapy, the therapeutic effect of the hormonal therapy should be monitored [see DRUG INTERACTIONS].
VIRAMUNE may decrease plasma concentrations of methadone by increasing its hepatic metabolism. Narcotic withdrawal syndrome has been reported in patients treated with VIRAMUNE and methadone concomitantly. Monitor methadone-maintained patients beginning nevirapine therapy for evidence of withdrawal and adjust methadone dose accordingly [see DRUG INTERACTIONS].
- Fat Redistribution
Inform patients that redistribution or accumulation of body fat may occur in patients receiving antiretroviral therapy and that the cause and long-term health effects of these conditions are not known at this time [see WARNINGS AND PRECAUTIONS].
Carcinogenesis, Mutagenesis, Impairment Of Fertility
Long-term carcinogenicity studies in mice and rats were carried out with nevirapine. Mice were dosed with 0, 50, 375 or 750 mg/kg/day for two years. Hepatocellular adenomas and carcinomas were increased at all doses in males and at the two high doses in females. In studies in which rats were administered nevirapine at doses of 0, 3.5, 17.5 or 35 mg/kg/day for two years, an increase in hepatocellular adenomas was seen in males at all doses and in females at the high dose. The systemic exposure (based on AUCs) at all doses in the two animal studies was lower than that measured in humans at the 200 mg twice daily dose. The mechanism of the carcinogenic potential is unknown.
However, in genetic toxicology assays, nevirapine showed no evidence of mutagenic or clastogenic activity in a battery of in vitro and in vivo studies. These included microbial assays for gene mutation (Ames: Salmonella strains and E. coli), mammalian cell gene mutation assay (CHO/HGPRT), cytogenetic assays using a Chinese hamster ovary cell line and a mouse bone marrow micronucleus assay following oral administration. Given the lack of genotoxic activity of nevirapine, the relevance to humans of hepatocellular neoplasms in nevirapine-treated mice and rats is not known.
Impairment Of Fertility
In reproductive toxicology studies, evidence of impaired fertility was seen in female rats at doses providing systemic exposure, based on AUC, approximately equivalent to that provided with the recommended clinical dose of VIRAMUNE.
Use In Specific Populations
Pregnancy Category B
There are no adequate and well-controlled trials of VIRAMUNE in pregnant women. The Antiretroviral Pregnancy Registry, which has been surveying pregnancy outcomes since January 1989, has not found an increased risk of birth defects following first trimester exposures to nevirapine. The prevalence of birth defects after any trimester exposure to nevirapine is comparable to the prevalence observed in the general population.
Severe hepatic events, including fatalities, have been reported in pregnant women receiving chronic VIRAMUNE therapy as part of combination treatment of HIV-1 infection. Regardless of pregnancy status, women with CD4+ cell counts greater than 250 cells/mm³ should not initiate VIRAMUNE unless the benefit outweighs the risk. It is unclear if pregnancy augments the risk observed in non-pregnant women [see BOXED WARNING].
VIRAMUNE should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Antiretroviral Pregnancy Registry
To monitor maternal-fetal outcomes of pregnant women exposed to VIRAMUNE, an Antiretroviral Pregnancy Registry has been established. Physicians are encouraged to register patients by calling (800) 258-4263.
No observable teratogenicity was detected in reproductive studies performed in pregnant rats and rabbits. The maternal and developmental no-observable-effect level dosages produced systemic exposures approximately equivalent to or approximately 50% higher in rats and rabbits, respectively, than those seen at the recommended daily human dose (based on AUC). In rats, decreased fetal body weights were observed due to administration of a maternally toxic dose (exposures approximately 50% higher than that seen at the recommended human clinical dose).
The Centers for Disease Control and Prevention recommend that HIV-1 infected mothers not breastfeed their infants to avoid risking postnatal transmission of HIV-1. Nevirapine is excreted in breast milk. Because of both the potential for HIV-1 transmission and the potential for serious adverse reactions in nursing infants, mothers should be instructed not to breastfeed if they are receiving VIRAMUNE.
The safety, pharmacokinetic profile, and virologic and immunologic responses of VIRAMUNE have been evaluated in HIV-1 infected pediatric subjects age 3 months to 18 years [see ADVERSE REACTIONS and Clinical Studies]. The safety and pharmacokinetic profile of VIRAMUNE has been evaluated in HIV-1 infected pediatric subjects age 15 days to less than 3 months [see ADVERSE REACTIONS and Clinical Studies].
The most frequently reported adverse events related to VIRAMUNE in pediatric subjects were similar to those observed in adults, with the exception of granulocytopenia, which was more commonly observed in children receiving both zidovudine and VIRAMUNE [see ADVERSE REACTIONS and Clinical Studies].
Clinical trials of VIRAMUNE did not include sufficient numbers of subjects aged 65 and older to determine whether elderly subjects respond differently from younger subjects. In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal or cardiac function, and of concomitant disease or other drug therapy.
In subjects with renal impairment (mild, moderate or severe), there were no significant changes in the pharmacokinetics of nevirapine. Nevirapine is extensively metabolized by the liver and nevirapine metabolites are extensively eliminated by the kidney. Nevirapine metabolites may accumulate in patients receiving dialysis; however, the clinical significance of this accumulation is not known. No adjustment in nevirapine dosing is required in patients with CrCL greater than or equal to 20 mL per min. The pharmacokinetics of nevirapine have not been evaluated in patients with CrCl less than 20 mL per min. In patients undergoing chronic hemodialysis, an additional 200 mg dose following each dialysis treatment is indicated [see DOSAGE AND ADMINISTRATION and CLINICAL PHARMACOLOGY].
Because increased nevirapine levels and nevirapine accumulation may be observed in patients with serious liver disease, do not administer VIRAMUNE to patients with moderate or severe (Child-Pugh Class B or C, respectively) hepatic impairment [see CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS, and CLINICAL PHARMACOLOGY].This monograph has been modified to include the generic and brand name in many instances.
Last reviewed on RxList: 2/6/2014
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